rs760319837

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000492.4(CFTR):c.944T>C(p.Phe315Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.54

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 3 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3552916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.944T>C	p.Phe315Ser	missense_variant	Exon 8 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.944T>C	p.Phe315Ser	missense_variant	Exon 8 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251272

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00124

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00103

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3

Aug 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the CFTR protein (p.Phe315Ser). This variant is present in population databases (rs760319837, gnomAD 0.1%). This missense change has been observed in individual(s) with CFTR-related metabolic syndrome (PMID: 23810505). ClinVar contains an entry for this variant (Variation ID: 455784). 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. 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F315S variant (also known as c.944T>C), located in coding exon 8 of the CFTR gene, results from a T to C substitution at nucleotide position 944. The phenylalanine at codon 315 is replaced by serine, an amino acid with highly dissimilar properties. This variant was detected in conjunction with a pathogenic mutation in CFTR in a Hispanic individual with a positive newborn screen but no manifestations of cystic fibrosis; the phase of the variants was not determined (Prach L et al. J Mol Diagn, 2013 Sep;15:710-22). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

CFTR-related disorder

Uncertain:2

Jun 01, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.944T>C variant is predicted to result in the amino acid substitution p.Phe315Ser. This variant has been reported, without a second CFTR variant, in an individual with CFTR-related metabolic syndrome (Prach et al. 2013. PubMed ID: 23810505). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:2

Sep 15, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.944T>C; p.Phe315Ser variant is reported in the medical literature in one individual with CFTR-related metabolic disorder (Prach 2013). The variant is listed in the dbSNP variant database (rs760319837) and in the Genome Aggregation Database in 45/277018 alleles, but is not listed in the ClinVar database. The phenylalanine at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Prach L et al. Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. J Mol Diagn. 2013 Sep;15(5):710-22. -

not specified

Uncertain:1

Aug 09, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.944T>C (p.Phe315Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of 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 0.00017 in 251272 control chromosomes in the gnomAD database, exclusively observed within the Latino subpopulation at a frequency of 0.0012. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0012 vs 0.013), allowing no conclusion about variant significance. c.944T>C has been reported in the literature in one newborn of Hispanic ethnicity with CFTR-related metabolic syndrome (Prach_2013). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23810505). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;.;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.36

T;T;T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.0

L;.;.;.;L

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;.;.;N;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;.;.;D;.

Sift4G

Uncertain

0.0020

D;.;.;D;.

Polyphen

0.45

P;.;.;.;.

Vest4

0.72

MutPred

0.66

Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);Loss of stability (P = 0.0137);.;Loss of stability (P = 0.0137);

MVP

0.99

MPC

0.0031

ClinPred

0.20

GERP RS

5.4

Varity_R

0.80

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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