rs151048781

chr7-117603730-G-Achr7-117603730-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5

The NM_000492.4(CFTR):c.2856G>A(p.Met952Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,728 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M952T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.76

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 Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 53580
• PM1: In a helix (size 25) in uniprot entity CFTR_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117603729-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 53579.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=7}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 7-117603730-G-A is Pathogenic according to our data. Variant chr7-117603730-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 596906.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2856G>A	p.Met952Ile	missense_variant	17/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2856G>A	p.Met952Ile	missense_variant	17/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251352 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461728 Hom.: 1 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2023	The p.M952I variant (also known as c.2856G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide position 2856. The methionine at codon 952 is replaced by isoleucine, an amino acid with highly similar properties. CFTR p.M952I (c.2586G>A or c.2586G>C) was originally identified in an individual with severe pulmonary disease, pancreatic insufficiency, and an elevated sweat chloride level; a second CFTR alteration was not identified (Desgeorges M et al. Hum. Genet., 1997 Aug;100:279-83). This variant was also detected in conjunction with pathogenic CFTR mutations in individuals with idiopathic chronic pancreatitis and congenital bilateral absence of the vas deferens (CBAVD) (Uzun S et al. Tohoku J. Exp. Med., 2005 Dec;207:279-85; Ratbi I et al. Hum. Reprod. 2007;22(5):1285-91; Steiner B et al. Hum. Mutat. 2011 Aug;32(8):912-20; Akinsal EC et al. Andrologia, 2018 Feb; Rudnik-Schöneborn S et al. Hum Reprod, 2021 02;36:551-559). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 952 of the CFTR protein (p.Met952Ile). This variant is present in population databases (rs151048781, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens or cystic fibrosis (PMID: 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 596906). 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%. This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 10875853), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 20, 2021

Variant summary: CFTR c.2856G>A (p.Met952Ile) results in a conservative amino acid change located in the ABC Transporter type 1, transmembrane domain of the encoded protein sequence. Another variant c.2856G>C, which causes the same missense change has been reported in the literature and databases with a majority consensus leaning towards pathogenic/likely pathogenic. Most publications do not clearly differentiate between these two at the nucleotide level of specification. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 251352 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (5.6e-05 vs 0.013), allowing no conclusion about variant significance. c.2856G>A has been reported in the literature in individuals predominantly affected with Congenital Bilateral Absence of the Vas Deferens (example, DeMeeus_1997, Gallati_2009, Havasi_2010, Ratbi_2007, Steiner_2011, Dayangac_2004) and settings of infertility (example, Rudnik-Schoneborn_2021). It has also been reported in individuals indicated to be affected with CF with non-informative genotypes (example, Desgeorges_1997, Kammesheidt_2006, Quint_2005). Furthermore, Terlizzi_2019 reports a patient, deltaF508/M952I, who had normal sweat chloride levels but it was unclear whether the patient could harbor other CFTR-Related Diseases such as CBAVD. These data indicate that the variant is likely to be associated with disease. At-least one co-occurrence, presumably in cis with another pathogenic variant has been reported (CFTR, G542X or CFTR, Y914X, phase not specified) in a patient with classic CF phenotype (Kammesheidt_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic in settings of CFTR-related disorders such as CBAVD. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;.;.;N;.
REVEL	Pathogenic	0.82
Sift	Benign	0.14	T;.;.;T;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.95
MutPred		0.88		Gain of catalytic residue at L957 (P = 0.0495);.;.;.;.;
MVP		1.0
MPC		0.0079
ClinPred		0.85	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.96

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: rs151048781; hg19: chr7-117243784;