rs397508804

Positions:

chr7-117536663-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000492.4(CFTR):c.859A>T(p.Asn287Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000807 in 1,611,112 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7O:1

Conservation

PhyloP100: 7.00

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 Likely_pathogenic. Variant got 7 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

PP5

Variant 7-117536663-A-T is Pathogenic according to our data. Variant chr7-117536663-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54069.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, not_provided=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.859A>T	p.Asn287Tyr	missense_variant	7/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.859A>T	p.Asn287Tyr	missense_variant	7/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248950

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134708

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458926

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725886

show subpopulations

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:5Other:1

Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM2_SUP, PM3, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2023	The p.N287Y variant (also known as c.859A>T), located in coding exon 7 of the CFTR gene, results from an A to T substitution at nucleotide position 859. The asparagine at codon 287 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was identified with Delta F508 in an individual with a clinical diagnosis of cystic fibrosis (Shrimpton AE et al. Hum Mutat, 1997;10:436-42). In vitro studies showed CFTR protein harboring N287Y has normal maturation, cell surface targeting, and channel gating. However, this variant increased internalization of the protein, leading to reduced expression on the cell surface (Silvis MR et al. J Biol Chem, 2003 Mar;278:11554-60). Additionally, this alteration was identified in an individual diagnosed with idiopathic chronic pancreatitis (Chang MC et al. Clin Genet, 2007 Jun;71:530-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2021	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 287 of the CFTR protein (p.Asn287Tyr). This variant is present in population databases (rs397508804, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 9401006). ClinVar contains an entry for this variant (Variation ID: 54069). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CFTR function (PMID: 12529365). 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 provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 15, 2017	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 15, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 20, 2024

Variant summary: CFTR c.859A>T (p.Asn287Tyr) results in a non-conservative amino acid change located in the ABC transporter type 1, 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 2.4e-05 in 252260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.859A>T has been reported in the literature in the compound heterozygous state together with p.Phe508del in an individual with a mild form of Cystic Fibrosis (Shrimpton_1997) and in the heterozygous state in two individuals with with idiopathic chronic pancreatitis (Chang_2007). The variant has also been observed in 2 additional patients: one referred for genetic testing for chronic pancreatitis, and the other was asymptomatic but had a 1st cousin with CF (internal LCA data). Both patients also tested positive for c.2052dupA (p.Gln685ThrfsX4; phase is unknown), a mutation known to be associated with pancreatic insufficient CF. The UMD database also reported the variant of interest in one CF patient who had c.1521_1523delCTT (p.Phe508del) on the other allele and also carried c.2052dup (p.Gln685ThrfsX4; phase not specified), suggesting that c.859A>T (p.Asn287Tyr) may not be the cause of CF in this patient if the two pathogenic variants (i.e. p.Gln685ThrfsX4 and p.Phe508del) were in trans. It is possible that p.Gln685ThrfsX4 may be in cis with p.Asn287Tyr given these two relatively uncommon variants (p.Gln685ThrfsX4 has an allele frequency of 2/119584 in ExAC) were found together in 3 individuals and co-segregated together in one family (internal LCA data). At least one publication reports experimental evidence evaluating an impact on protein function (Silvis_2003). In these experiments, the variant did not exhibit a folding defect, as evidenced by similar maturation kinetics to the wild type CFTR protein. However, there was roughly 50% of the variant protein located at the plasma membrane at the steady state relative to wild type CFTR. Cholride transport was reduced in proportion to altered cell surface CFTR, but the single-channel properties of the variant were similar to those of the wild type. Biotinylation experiments showed that the variant protein was internalized approximately twice as fast as wild type CFTR, which is expected to alter its distribution between the plasma membrane and intracellular compartments, reducing its expression at the cell surface. The following publications have been ascertained in the context of this evaluation (PMID: 34740355, 17539902, 9401006, 12529365, 16339147, 25735457). ClinVar contains an entry for this variant (Variation ID: 54069). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2023

Published functional studies suggest a damaging effect: increased endocytic trafficking and lower cell-surface density, but no effect on biosynthesis and targeting to the cell surface (PMID: 12529365); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25735457, 26003067, 24561283, 19810821, 17235394, 16339147, 16049310, 17539902, 25404111, 22138491, 28603918, 17098482, 9401006, 12529365) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

D;.;.;D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Uncertain

0.099

MutationAssessor

Benign

1.0

L;.;.;.;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;.;.;N;.

REVEL

Pathogenic

0.69

Sift

Benign

0.37

T;.;.;T;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.74

P;.;.;.;.

Vest4

0.63

MutPred

0.77

Loss of disorder (P = 0.0591);Loss of disorder (P = 0.0591);Loss of disorder (P = 0.0591);.;Loss of disorder (P = 0.0591);

MVP

0.98

MPC

0.0039

ClinPred

0.67

GERP RS

5.1

Varity_R

0.40

gMVP

0.86

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