rs148783445

chr7-117666998-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000492.4(CFTR):c.4333G>A(p.Asp1445Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1445D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:2
• Conservation: PhyloP100: 9.12

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02589032).
• BP6: Variant 7-117666998-G-A is Benign according to our data. Variant chr7-117666998-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53941.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.4333G>A	p.Asp1445Asn	missense_variant	27/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.4333G>A	p.Asp1445Asn	missense_variant	27/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000737 AC: 112 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250898 Hom.: 0 AF XY: 0.000266 AC XY: 36 AN XY: 135576

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 114 AN XY: 727162

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000713 AC XY: 53 AN XY: 74380

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.00100

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 23, 2023	The variant has been reported in a child with an elevated sweat chloride test, chronic cough, and pancreatic insufficiency; a second CFTR variant was not identified. The frequency of this variant in the general population, 0.002 (50/24958 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with CF (PMIDs: 10923036 (2000), 15858154 (2005), 32819855 (2020), 36409994 (2022)), pancreatitis (PMIDs: 17003641 (2006), 23951356 (2013)), pulmonary disease (PMIDs: 20722470 (2010), 33432171 (2021), 34996830 (2022)), and infertility (PMIDs: 31872980 (2020), 32357917 (2020)). One functional study in yeast has shown that this variant does not interfere with AMPK interaction (PMID: 10862786 (2000)), however further research is needed. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	The CFTR c.4333G>A; p.Asp1445Asn variant (rs148783445) is reported in the medical literature in individuals affected with cystic fibrosis or other CFTR-related disorders, but without clear association with disease (Castellani 2017, Claustres 2000, Keiles 2006, Masson 2013, Mieusset 2020, Picca 2010, Schrijver 2005, Zeiger 2020). This variant is reported in ClinVar (Variation ID: 53941), and is found in the general population with an overall allele frequency of 0.04% (106/282286 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1445 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.537). However, given the lack of specific clinical and functional data, the significance of the p.Asp1445Asn variant is uncertain at this time. References: Castellani C et al. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. Arch Dis Child. 2017 Jul;102(7):644-646. PMID: 26755536. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. PMID: 10923036. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Masson E et al. A Conservative Assessment of the Major Genetic Causes of Idiopathic Chronic Pancreatitis: Data from a Comprehensive Analysis of PRSS1, SPINK1, CTRC and CFTR Genes in 253 Young French Patients. PLoS One. 2013; 8(8): e73522. PMID: 23951356. Mieusset R et al. Male partners of infertile couples with congenital unilateral absence of the vas deferens are mainly non-azoospermic. Andrology. 2020 May;8(3):645-653. PMID: 31872980. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010 Jan;9(1):29-35. PMID: 19897426. Schrijver I et al. Diagnostic Testing by CFTR Gene Mutation Analysis in a Large Group of Hispanics. J Mol Diagn. 2005 May; 7(2): 289–299. PMID: 15858154. Zeiger AM et al. Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico. Pediatr Pulmonol. 2020 Feb;55(2):533-540. PMID: 31665830. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	Observed in individuals with cystic fibrosis and other CFTR-related disorders, without a second CFTR variant reported (Claustres 2000, Schrijver 2005, Keiles 2006, Trujillano 2015); Observed with a pathogenic variant, phase unknown, in an infant without cystic fibrosis and a normal sweat chloride result (Castellani 2017); Published functional studies are inconclusive: normal interaction with AMPK, the clinical significance of which is unknown (Hallows 2000); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 15858154, 17003641, 10923036, 26436105, 22995991, 23951356, 25735457, 19897426, 26847993, 10862786, 32357917, 26755536, 20722470, 34426522, 33946859, 31665830, 31682332, 34996830, 32819855) -

Cystic fibrosis Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 21, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 22, 2019	This CFTR variant has been previously identified in patients with features of cystic fibrosis, but also in one infant with a normal sweat chloride concentration. The clinical significance of this variant is classified as uncertain by multiple submitters in ClinVar. CFTR c.4333G>A (rs148783445) has been identified in a large population datasets and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African subpopulation (gnomAD: 50/24958 alleles; 0.02%, no homozygotes). Of three bioinformatics tools queried, two predict that the substitution would be possibly damaging, while one predicts that it would be tolerated. The aspartic acid residue at this position is conserved across many, but not all of the species assessed. We consider the clinical significance of c.4333G>A to be uncertain at this time. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 08, 2023

Variant summary: CFTR c.4333G>A (p.Asp1445Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251444 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00034 vs 0.013), allowing no conclusion about variant significance. c.4333G>A has been reported in the literature in individuals affected with or suspected to exhibit symptoms of Cystic Fibrosis and Cystic Fibrosis related disorders (e.g. Claustres_2000, Schrijver_2005, Trujilliano_2015, Zeigler_2020, da Silva Filho_2020). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The variant has also been reported in compound heterozygosity with a well-known pathogenic mutation (CFTR F508del) in at least one infant who had a normal sweat chloride test (Castellani_2016). In addition, the variant has been reported in individuals affected with pancreatitis (Keiles_2006, Masson_2013), sarcoidosis (Makrythanasis_2010), and congenital unilateral absence of vas deferens (CUAVD; Mieusset_2019), but without strong evidence for causality. One publication reports experimental evidence indicating that the variant does not disrupt interactions with AMPK in a yeast-based assay (Hallows_2000), however the clinical significance of this finding is not clear. The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 26755536, 32357917, 10923036, 10862786, 17003641, 26847993, 20722470, 26354092, 23951356, 31872980, 19897426, 15858154, 31682332, 26436105, 31665830, 32819855). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters classified the variant as uncertain significance and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

The CFTR c.4333G>A variant is predicted to result in the amino acid substitution p.Asp1445Asn. This variant has been reported in individuals with cystic fibrosis or other CFTR-related disorders, although it is unclear if a second CFTR variant was present or if zygosity was known (Claustres et al. 2000. PubMed ID: 10923036; Schrijver et al. 2005. PubMed ID: 15858154; Trujilliano et al. 2015. PubMed ID: 26436105; da Silva Filho et al. 2020. PubMed ID: 32819855; Zeigler et al. 2020. PubMed ID: 31665830). This variant has been reported in the heterozygous state in individuals with pancreatitis, without additional evidence to support its pathogenicity (Keiles et al. 2006. PubMed ID: 17003641; Masson et al. 2013. PubMed ID: 23951356). This variant has also been reported in an individual who had a normal sweat chloride test and also carried the common, pathogenic CFTR c.1521_1523delCTT (p.Phe508del) variant (Castellani et al. 2016. PubMed ID: 26755536). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.97	N;N;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.012	D;D;.
Polyphen		0.97	D;.;.
Vest4		0.25
MVP		0.99
MPC		0.0042
ClinPred		0.069	T
GERP RS		5.5
Varity_R		0.38
gMVP		0.52

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: rs148783445; hg19: chr7-117307052; COSMIC: COSV50042744;