rs73215912

Variant names:

• chr7-117542024-A-C
• rs73215912
• NM_000492.4:c.1125A>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. 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:5 U:4 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 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=3, Uncertain_significance=3, Pathogenic=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1125A>C	p.Leu375Phe	missense_variant	Exon 9 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1125A>C	p.Leu375Phe	missense_variant	Exon 9 of 27	1	NM_000492.4	ENSP00000003084.6

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:5 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:4 Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 08, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 08, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (J&eacute;z&eacute;quel P et al. Hum. Genet., 1996 Apr;97:548-9; D&ouml;rk T et al. Hum Genet, 1997 Sep;100:365-77; J&eacute;z&eacute;quel 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 (Fa&agrave; 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. -

Oct 20, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 14, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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%. For these reasons, this variant has been classified as Pathogenic. -

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

Sep 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1125A>C; p.Leu375Phe variant (rs73215912, ClinVar Variation ID: 53196), is reported in multiple individuals with congenital bilateral absence of the vas deferens (CBAVD) or pancreatitis, including some individuals with a second pathogenic CFTR variant (Chiang 2008, Jezequel 1996, Jezequel 2000, Li 2012, Mieusset 2020, Palermo 2016, Wu 2005). This variant is found in the non-Finnish European population with an allele frequency of 0.0088% (10/113116 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another amino acid substitution at this codon (c.1124T>C; p.Leu375Ser) has been reported in an individual with CBAVD (Wang 2020). Computational analyses predict that Leu375Phe variant is deleterious (REVEL: 0.8). Based on available information, this variant is considered to be likely pathogenic-mild. References: 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. PMID: 18796364. 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. PMID: 8834261. Jezequel P et al. Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. Mol Hum Reprod. 2000 Dec;6(12):1063-7. PMID: 11101688. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23. PMID: 22483971. Mieusset R et al. Male partners of infertile couples with congenital unilateral absence of the vas deferens are mainly non-azoospermic. Andrology. 2020 May;8(3):645-653. PMID: 31872980. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. PMID: 27171515. Wang H et al. Genetic diagnosis and sperm retrieval outcomes for Chinese patients with congenital bilateral absence of vas deferens. Andrology. 2020 Sep. PMID: 32020786. 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. PMID: 15905293. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Sep 19, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 24, 2023

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.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. -

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
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;