rs151048781

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000017 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 9.76

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 50) in uniprot entity CFTR_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

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: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2856G>A	p.Met952Ile	missense_variant	17/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2856G>A	p.Met952Ile	missense_variant	17/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251352

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135830

show subpopulations

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:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727160

show subpopulations

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.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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. -

not provided

Uncertain:3

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 29, 2023	PP3, PM2_moderate, PS1_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2024	CFTR c.2856G>A has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; p.(M952I), nucleotide change not specified, has been observed in individuals with inconclusive diagnoses or CFTR-related metabolic syndrome identified subsequent to newborn screening, congenital absence of the vas deferens, and cystic fibrosis, including an individual with a positive sweat chloride test and two additional CFTR variants reported (PMID: 28544683, 16980811, 31005549, 21520337, 28603918, 20100616, 16272798, 33374015, Turkyilmaz and Yarali, 2021); This variant is associated with the following publications: (PMID: 20977904, 10875853, 17003641, 14551163, 34949556, 27026144, Sorrentino(2024)_article, 28544683, 16980811, 31005549, 21520337, 28603918, 20100616, 16272798, 33374015, Turkyilmaz2021[CaseReport]) -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 21, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.0

M;.;.;.;.

PrimateAI

Uncertain

0.63

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over