rs73215912

chr7-117542024-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5 O:1
• Conservation: PhyloP100: 1.04

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 21) in uniprot entity CFTR_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000492.4
• 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, Uncertain_significance=4, Pathogenic=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1125A>C	p.Leu375Phe	missense_variant	9/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1125A>C	p.Leu375Phe	missense_variant	9/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152238 Hom.: 0 Cov.: 32

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: 10 AN: 250100 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135368

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.: 0 Cov.: 23 AF XY: 0.0000989 AC XY: 68 AN XY: 687310

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: 5 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74496

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.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:4 Other:1

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. -
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)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 20, 2020	- -

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	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
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	D
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

Other links and lift over

dbSNP: rs73215912; hg19: chr7-117182078;