7-117603730-G-A

Variant names:

• chr7-117603730-G-A
• rs151048781
• NM_000492.4:c.2856G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PP2 PP3_Strong

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 the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M952T) has been classified as Uncertain significance.

• 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:6 U:3 B:1
• Conservation: PhyloP100: 9.76
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 30 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2856G>A	p.Met952Ile	missense	Exon 17 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2856G>A	p.Met952Ile	missense	Exon 17 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.2856G>A	p.Met952Ile	missense	Exon 17 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.2766G>A	p.Met922Ile	missense	Exon 16 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251352 AF XY: 0.0000294

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.000425 AC: 19 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Benign:1

Apr 07, 2025

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as likely benign (PM2, PP5, BS2_supporting, BP6).

Feb 10, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Feb 01, 2013

Arcensus

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 17, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_moderate, PS1_moderate

Jul 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 20, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.82
Sift	Benign	0.14	T
Sift4G	Pathogenic	0.0	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
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs151048781; hg19: chr7-117243784;