rs397508270

chr7-117590367-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):c.1694A>G(p.Asp565Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,603,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D565Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 O:1
• Conservation: PhyloP100: 8.64

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 7-117590367-A-G is Pathogenic according to our data. Variant chr7-117590367-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53344.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=1, Pathogenic=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1694A>G	p.Asp565Gly	missense_variant	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1694A>G	p.Asp565Gly	missense_variant	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1450960 Hom.: 0 Cov.: 30 AF XY: 0.00000831 AC XY: 6 AN XY: 721658

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

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: 0.0000136

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:3 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2021	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 565 of the CFTR protein (p.Asp565Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 9620832, 21520337). ClinVar contains an entry for this variant (Variation ID: 53344). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 12719375). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2023	The p.D565G variant (also known as c.1694A>G), located in coding exon 13 of the CFTR gene, results from an A to G substitution at nucleotide position 1694. The aspartic acid at codon 565 is replaced by glycine, an amino acid with similar properties. This variant has been identified in several individuals with symptoms of cystic fibrosis or CFTR-related disorders in conjunction with p.R668C; in some individuals, these variants were shown to occur in cis (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7; Pagani F et al. Hum Mol Genet, 2003 May;12:1111-20). Analysis of exon skipping in 12 individuals with p.R688C in cis demonstrated increased exon skipping compared to controls in half, with the remaining half with similar levels to controls (Pagani F et al. Hum Mol Genet, 2003 May;12:1111-20). This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 22, 2023

Variant summary: CFTR c.1694A>G (p.Asp565Gly) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1694A>G has been reported in the literature in a heterozygous state in individuals affected with congenital bilateral absence of the vas deferens (CBAVD), disseminated bronchiectasis, pneumonia, nasal polyps, idiopathic chronic pancreatitis, and cystic fibrosis, but was also found in multiple unaffected individuals (e.g. Kanavakis_1998, Tzetis_2001, Pagani_2003, Steiner_2011, Raraigh_2022). In several of these cases and controls the variant was noted to co-occur in complex (i.e. in cis) with the c.2002C>T (p.Arg668Cys) variant (Pagani_2003). In addition, the variant was also reported in an individual affected with assumed CBAVD (i.e. obstructive azoospermia), who also carried a common pathogenic variant (Ooi_2014), however in this patient sweat chloride concentration was below 60 mmol/L, and nasal potential difference (NPD) was indicated to be normal. These data do not allow any conclusion about variant significance. At least one publication reported experimental evidence, and demonstrated that it resulted in a partial exon skipping in nasal epithelial cells derived from individuals carrying the variant, as well as in an in vitro minigene system (Pagani_2003). The variant might affect exonic splicing regulatory elements, as the extent of the splicing defect caused by the D565G variant in the minigene system was highly dissimilar among the five transfected cell lines, and the degree of splice defect was also heavily influenced by the co-transfection of various splicing factors (Pagani_2003). Therefore, these data do not allow clear conclusions about the variant effect in vivo. The following publications have been ascertained in the context of this evaluation (PMID: 12719375, 18456578, 21520337, 11810271, 9620832, 24697796, 17076271, 34782259). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;.;D;.
REVEL	Pathogenic	0.95
Sift	Benign	0.049	D;.;D;.
Sift4G	Uncertain	0.010	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.97
MutPred		0.85		Gain of MoRF binding (P = 0.0533);.;.;.;
MVP		1.0
MPC		0.0042
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs397508270; hg19: chr7-117230421;