rs73215912

Positions:

chr7-117542024-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000492.4(CFTR):c.1125A>C(p.Leu375Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000959 in 1,522,558 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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5O:1

Conservation

PhyloP100: 1.04

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 7-117542024-A-C is Pathogenic according to our data. Variant chr7-117542024-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53196.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=4, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1125A>C	p.Leu375Phe	missense_variant	9/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1125A>C	p.Leu375Phe	missense_variant	9/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250100

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135368

show subpopulations

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:

0.0000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

141

AN:

1370202

Hom.:

Cov.:

AF XY:

0.0000989

AC XY:

AN XY:

687310

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.0000225

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:

0.000129

Gnomad4 OTH exome

AF:

0.000105

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74496

show subpopulations

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000465

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:4Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 08, 2020	CFTR c.1125A>C has been identified in multiple individuals with congenital absence of the vas deferens. There is an entry in ClinVar for this variant. This CFTR variant (rs73215912) is rare (<0.1%) in a large population dataset (gnomAD: 10/250100 total alleles; 0.004%; no homozygotes). Three bioinformatic tools queried predict that this substitution would probably be damaging and the leucine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of c.1125C>A to be uncertain at this time. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 375 of the CFTR protein (p.Leu375Phe). This variant is present in population databases (rs73215912, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital absence of vas deferens in the homozygous state or in combination with another CFTR variant (PMID: 8834261, 9272157, 11101688, 15905293, 18796364). 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: 53196). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 2023	The p.L375F variant (also known as c.1125A>C), located in coding exon 9 of the CFTR gene, results from an A to C substitution at nucleotide position 1125. The leucine at codon 375 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in multiple men with congenital unilateral and bilateral absence of the vas deferens and a second CFTR alteration, including two cases with phase confirmed in trans (Jézéquel P et al. Hum. Genet., 1996 Apr;97:548-9; Dörk T et al. Hum Genet, 1997 Sep;100:365-77; Jézéquel P et al. Mol. Hum. Reprod., 2000 Dec;6:1063-7; Wu CC et al. Hum Reprod, 2005 Sep;20:2470-5; Chiang HS et al. J. Formos. Med. Assoc., 2008 Sep;107:736-40). This alteration has also been observed in individuals with cystic fibrosis or recurrent pancreatitis (Faà V et al. J Mol Diagn, 2006 Sep;8:499-503; Palermo JJ et al. Pancreas, 2016 10;45:1347-52). 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 may contribute to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 19, 2023

- -

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

Apr 24, 2023

Variant summary: CFTR c.1125A>C (p.Leu375Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250222 control chromosomes, predominantly at a frequency of 8.8e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (4.4e-05 vs 0.013), allowing no conclusion about variant significance. c.1125A>C has been reported in the literature in individuals affected with Congenital Unilateral- (Jezequel_2000) and Bilateral Absence of the Vas Deferens (Dork_1997, Jezequel_2000, Wu_2005) and azoospermia (Mieusset_2019). These data indicate that the variant is likely to be associated with disease. The variant has also been reported in a patient with cystic fibrosis (Faa_2006) and in an individual with chronic pancreatitis (Palermo_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 22, 2018

The CFTR c.1125A>C; p.Leu375Phe variant (rs73215912), is reported in the literature in the compound heterozygous state in multiple individuals affected with congenital bilateral absence of vas deferens (Chiang 2008, Jezequel 1996, Wu 2005), and in the heterozygous state in unaffected individuals (Berg 2013, Dorfman 2010, Palermo 2016). This variant is reported in ClinVar (Variation ID: 53196), and is found in the non-Finnish European population with an overall allele frequency of 0.01% (11/111,140 alleles) in the Genome Aggregation Database. The leucine at codon 375 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu375Phe variant is uncertain at this time. References: Berg JS et al. An informatics approach to analyzing the incidentalome. Genet Med. 2013 Jan;15(1):36-44. Chiang HS et al. CFTR mutation analysis of a Caucasian father with congenital bilateral absence of vas deferens, a Taiwanese mother, and twins resulting from ICSI procedure. J Formos Med Assoc. 2008 Sep;107(9):736-40. Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 May;77(5):464-73. Jezequel P et al. Identification of a novel mutation in CFTR gene exon 8 (L375F) in a CUAVD phenotype. Hum Genet. 1996 Apr;97(4):548-9. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. Wu CC et al. Mutation spectrum of the CFTR gene in Taiwanese patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2005 Sep;20(9):2470-5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.1

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

D;.;.;D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.90

MutPred

0.73

Gain of ubiquitination at K377 (P = 0.0668);Gain of ubiquitination at K377 (P = 0.0668);Gain of ubiquitination at K377 (P = 0.0668);.;Gain of ubiquitination at K377 (P = 0.0668);

MVP

1.0

MPC

0.015

ClinPred

0.82

GERP RS

1.2

Varity_R

0.78

gMVP

0.93

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