rs397508553

chr7-117614654-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000492.4(CFTR):c.3409A>G(p.Met1137Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,612,462 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. M1137I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 O:1
• Conservation: PhyloP100: 9.14

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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 chr7-117614655-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 7-117614654-A-G is Pathogenic according to our data. Variant chr7-117614654-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53733.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3409A>G	p.Met1137Val	missense_variant	21/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3409A>G	p.Met1137Val	missense_variant	21/27	1	NM_000492.4	P2
	ENST00000456270.1	n.177+1575T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251148 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1460312 Hom.: 0 Cov.: 30 AF XY: 0.0000427 AC XY: 31 AN XY: 726498

Gnomad4 AFR exome AF: 0.00

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: 0.0000504

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152150 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2023	The p.M1137V variant (also known as c.3409A>G), located in coding exon 21 of the CFTR gene, results from an A to G substitution at nucleotide position 3409. The methionine at codon 1137 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in individuals with cystic fibrosis or congenital bilateral absence of the vas deferens who carried an additional pathogenic/likely pathogenic variant (Iuliano L et al. Am J Clin Nutr, 2009 Sep;90:477-84; El-Seedy A et al. Hum Mutat, 2012 Nov;33:1557-65; Jabr S et al. Prostaglandins Leukot Essent Fatty Acids, 2013 Aug;89:121-6; Clarke LA et al. Hum Mutat, 2019 Mar;40:326-334). However, it has also been detected in trans with p.F508del in a neonate who had elevated immunoreactive trypsinogen concentration, but normal sweat chloride level (Castellani C et al. J Med Genet, 2001 Mar;38:202-5). Based on internal structural analysis, M1137V is more disruptive than several internally pathogenic variants within the same transmembrane domain (Fiedorczuk K et al. Cell, 2022 Jan;185:158-168.e11). In a functional study, M1137V did not affect protein maturation, but significantly reduced cAMP-activated whole cell chloride currents (Vankeerberghen A et al. FEBS Lett., 1998 Oct;437:1-4). 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, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 27, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1137 of the CFTR protein (p.Met1137Val). This variant is present in population databases (rs397508553, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis, bronchiectasis, congenital bilateral absence of vas deferens and hypertrypsinaemia (PMID: 7543317, 9921909, 11303517, 12454843, 22678879, 25910067, 26436105). ClinVar contains an entry for this variant (Variation ID: 53733). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 26436105). 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. -

not specified Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2023	Variant summary: CFTR c.3409A>G (p.Met1137Val) results in a conservative amino acid change located in the transmembrane domain (IPR011527) of 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 3.6e-05 in 252866 control chromosomes (gnomAD v2.1, and publication data). c.3409A>G has been reported in the literature in compound heterozygous individuals affected with cystic fibrosis (CF) who carried a pathogenic variant in trans (e.g. Clarke_2018, Iuliano_2009), but was also reported in an individual with neonatal hypertrypsinaemia, but normal sweat test, who was compound heterozygous for the variant and the delta508 allele (Castellani_2001). The variant was also found in a patient diagnosed with congenital bilateral absence of the vas deferens (CBAVD), who was a compound heterozygote with a complex allele classified as pathogenic for CFTR-related disorders by our lab (El-Seedy_2012). In addition, the variant was reported in individuals affected with CF-related- or unspecified phenotypes (e.g. Durno_2002, El-Seedy_2012, Green_2010, Bombieri_1998, Trujillano_2015, Castellani_2001, Eski_2019 [No PMID]), however without strong evidence for causality (i.e. lack of second CFTR variant and co-segregation evidence). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased channel activity, but no visible effect on protein maturation (Vankeerberghen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 7543317, 9921909, 8644755, 9804160, 22678879, 11303517, 20932301, 25910067, 12454843, 19587087, 26436105, 11845002, 30488522). Five other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (n=2) or VUS (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 23, 2020	- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 21, 2023

- -

Infertility disorder Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Mar 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.8	L;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;.;.;N;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	D;.;.;D;.
Sift4G	Uncertain	0.013	D;.;.;D;.
Polyphen		0.61	P;.;.;.;.
Vest4		0.94
MutPred		0.91		Gain of helix (P = 0.2294);.;.;.;.;
MVP		1.0
MPC		0.0055
ClinPred		0.33	T
GERP RS		5.9
Varity_R		0.78
gMVP		0.92

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: rs397508553; hg19: chr7-117254708;