7-117548758-G-T

Position:

• chr7-117548758-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000492.4(CFTR):​c.1327G>T​(p.Asp443Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,612,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D443V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:5
• Conservation: PhyloP100: 2.77

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117548758-G-T is Pathogenic according to our data. Variant chr7-117548758-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53229.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Pathogenic=8, Uncertain_significance=5}. Variant chr7-117548758-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1327G>T	p.Asp443Tyr	missense_variant	10/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.222-6219C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1327G>T	p.Asp443Tyr	missense_variant	10/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000264 AC: 64 AN: 242156 Hom.: 0 AF XY: 0.000297 AC XY: 39 AN XY: 131380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000600 AC: 876 AN: 1460654 Hom.: 0 Cov.: 36 AF XY: 0.000586 AC XY: 426 AN XY: 726584

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.000614

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74484

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000373 Hom.: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:9 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 18, 2018	The CFTR c.1327G>T (p.Asp443Tyr) missense variant has been reported in a compound heterozygous state in five individuals with chronic sinusitis and bronchitis and in a heterozygous state in one proband with congenital uni- or bilateral absence of the vas deferens (de Meeus et al. 1997; Mieusset et al. 2016). The p.Asp443Tyr variant has been reported as part of a complex allele, in cis with c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys) in 57 probands in a compound heterozygous state and in three probands in a heterozygous state (El-Seedy et al. 2012; Abou Alaiwa et al. 2014). Abramowicz et al. (2000) reported the p.[Asp443Tyr;Gly576Ala;Arg668Cys] variant in a compound heterozygous state in a fetus with hyperechoic bowel, a sibling with a history of lower respiratory tract infection and slightly raised sweat chloride, and in an asymptomatic sibling. The p.[Asp443Tyr;Gly576Ala;Arg668Cys] complex allele has been reported in four of 1,423 controls. The p.Asp443Tyr variant is reported at a frequency of 0.000461 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies indicate that p.[Asp443Tyr;Gly576Ala;Arg668Cys] alters CFTR maturation and chloride conductance but retains some residual function, which is consistent with mild or moderate phenotypes. Based on the evidence, the p.Asp443Tyr variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22678879; 29805046) - PS3_supporting.The c.1327G>T;p.(Asp443Tyr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 53229; PMID: 21520337; PMID: 10922395; PMID: 22678879; PMID: 23951356; PMID: 15126740; PMID: 32512765; PMID: 32172930) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (ABC_tran) - PM1. The variant is present at low allele frequencies population databases (rs147422190 – gnomAD 0.002595%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp443Tyr) was detected in trans with a pathogenic variant (PMID: 21520337) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 25133958; 20186691) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern - (PMID: 21520337) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2023	The p.D443Y variant (also known as c.1327G>T), located in coding exon 10 of the CFTR gene, results from a G to T substitution at nucleotide position 1327. The aspartic acid at codon 443 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been described as part of a complex allele (p.[D443Y;G576A;R668C] or p.[D443Y;G576A]) in individuals with CFTR-related disorders, including congenital absence of the vas deferens (CAVD) and chronic pancreatitis; a second alteration was not always detected, nor phase (cis vs. trans) described (Bombieri C et al. J. Cyst. Fibros., 2011 Jun;10 Suppl 2:S86-102; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20; Masson E et al. PLoS ONE, 2013 Aug;8:e73522). In vitro functional studies showed that this alteration affects protein maturation. In one study, p.D443Y showed decreased chloride channel activity when co-expressed with p.G576A and p.R668C, but not when expressed alone in cultured cells (El-Seedy et al. Hum Mutat. 2012; 33(11);15557-65). In another study, this variant showed decreased chloride channel activity when expressed alone (Raraigh KS et al. Am. J. Hum. Genet. 2018 Jun;102(6):1062-1077). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2020	Variant summary: CFTR c.1327G>T (p.Asp443Tyr) results in a non-conservative amino acid change located in the ABC transporter-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 242986 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Classic or Non-Classic Cystic Fibrosis, allowing no conclusion about variant significance. This variant has also been reported to form a haplotype with two other variants, namely, c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys). This complex haplotype c.[1327G>T;1727G>C;2002C>T] (p.[Asp443Tyr;Gly576Ala;Arg668Cys]), has been reported to be pathogenic for CFTR-RD. When ascertained conservatively for its occurrence in isolation, c.1327G>T alone (without the complex haplotype) has been reported in the literature in a compound heterozygous state with other pathogenic CFTR alleles in multiple individuals affected with features of sweat chloride positive classic Cystic Fibrosis, Non-classic Cystic Fibrosis such as CBAVD and settings of infertility (example, Claustres_2000, Steiner_2011, Viville_2000, Morea_2005). However, non-reporting of the other two variants that would constitute a complex allele in these reports cannot be entirely ruled out. Nevertheless, these data indicate that this variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function in isolation as well as part of the complex haplotype. The most pronounced isolated variant effect reports conflicting findings between studies ranging from no effect (El-Seedy_2012) to intermediate levels (Raraigh_2018) of chloride channel function (approximately 50% of WT levels) and a moderate alteration of CFTR maturation and localization (El-Seedy_2012). In one of these studies, the authors concluded that the combination of p.Gly576Ala and p.Arg668Cys affecting chloride channel activity coupled with p.Asp443Tyr effecting protein maturation would account for the pathogenicity of the overall haplotype (El-Seedy_2012). In contrast however, c.1727G>C and c.2002C>T have been reported as non-CF causing in isolation based on a large study evaluating the functional consequences of CFTR variants (Sosnay_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2, Likely pathogenic, n=3, and VUS, n=1). Some of these submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant in isolation was classified as pathogenic for CFTR-related disorders. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 443 of the CFTR protein (p.Asp443Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in trans with a pathogenic variant in individuals affected with congenital absence of the vas deferens (CAVD) (PMID: 21520337). Additionally, this variant frequently occurs in cis with the missense variants p.Gly576Ala and p.Arg668Cys. This haplotype has been reported in individuals affected by CFTR-related diseases including CAVD, idiopathic chronic pancreatitis (ICP), chronic sinusitus, and bronchiectasis (PMID: 10922395, 21520337, 22678879, 23951356, 15126740). ClinVar contains an entry for this variant (Variation ID: 53229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR protein function (PMID: 22678879). Furthermore, when this variant occurs in combination with p.Gly576Ala and p.Arg668Cys, CFTR chloride channel conductance is decreased. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM3_STR, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 20, 2020	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -

not provided Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 17, 2020	The CFTR c.1327G>T; p.Asp443Tyr variant (rs147422190), is described in the literature in several individuals with CBAVD who carry a pathogenic severe variant on the opposite allele (de Meeus 1998). This variant is often associated with other variants in cis (G576A, R668C) as a complex allele, and as such is reported to cause a wide range of symptoms including individuals who are asymptomatic even with a pathogenic severe allele on the opposite chromosome, CBAVD, idiopathic pancreatitis, disseminated bronchiectasis, fetal bowel anomaly, and chronic sinus disease (El-Seedy 2012). This variant is classified as a variant of varying clinical consequences in the CFTR2 database (see link), and is reported in ClinVar (Variation ID: 53229). It is found in the general European population with an allele frequency of 0.05% (60/123724 alleles) in the Genome Aggregation Database, but may be a low quality site in this database. The aspartate at codon 443 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Based on available information, this variant is considered to be mildly pathogenic for CFTR-related disorders. References: CFTR2 database: https://cftr2.org de Meeus A et al. Genetic findings in congenital bilateral aplasia of vas deferens patients and identification of six novel mutatations. Mutations in brief no. 138. Online. Hum Mutat. 1998;11(6):480. El-Seedy A et al. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum Mutat. 2012 Nov;33(11):1557-65. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 02, 2023	In the published literature, this variant has been reported as part of a complex allele (PMIDs: 10601093 (1999), 10922395 (2000), 19812525 (2010), 26900683 (2016), and 32773111 (2020)) and observed in CFTR-Related disorders, mostly CBAVD and pancreatitis (PMIDs: 10200050 (1998), 10601093 (1999), 19812525 (2000), 15097853 (2004), 16126774 (2005), 17413420 (2007), 17975025 (2007), 17329263 (2007), 20100616 (2010), 21520337 (2011), 22678879 (2012), 23951356 (2013), 26990548 (2016), and 26946416 (2017)). In vitro functional studies have shown that this variant does not affect chloride channel activity, but it may affect CFTR protein maturation and subcellular localization (PMID: 22678879 (2012)). Another study indicates that this variant is associated with 53.2% of wild type CFTR function that may not be disease-causing (PMID: 29805046 (2018)). The frequency of this variant in the general population, 0.00048 (60/123724 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CFTR: PM3:Very Strong, PM2 -

CFTR-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Mar 26, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 01, 2019	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2014

The Asp443Tyr variant in CFTR has been reported in >50 compound heterozygous ind ividuals with varying clinical diagnoses, including congenital bilateral absence of the van deferens (CBAVD), diffuse bronchiectasis, idiopathic pancreatitis, a nd cystic fibrosis (de Meeus 1997, El-Seedy 2012); however most of these individ uals carried one or more CFTR variants in cis with this variant. This variant be en identified in 2/8588 European American and 2/4400 African American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs147422190). Functional data suggest that the Asp443Tyr variant may alter CFT R protein maturation (El-Seedy 2012), however this in vivo assay may not accurat ely reflect biological function. Computational prediction tools and evolutionary conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp443Tyr variant is uncertain. -

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Apr 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.90	P;.
Vest4		0.79
MVP		0.99
MPC		0.0097
ClinPred		0.57	D
GERP RS		2.5
Varity_R		0.84
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147422190; hg19: chr7-117188812;