rs397508725

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The ENST00000003084.11(CFTR):c.473G>A(p.Ser158Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S158T) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:9

Conservation

PhyloP100: 9.52

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.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117531098-G-A is Pathogenic according to our data. Variant chr7-117531098-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618959.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.473G>A	p.Ser158Asn	missense_variant	4/27	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.473G>A	p.Ser158Asn	missense_variant	4/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

249072

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134548

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:

0.000593

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1460566

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726530

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:

0.000476

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:

152266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74454

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Oct 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.S158N in CFTR (NM_000492.4) has been reported previously in both trans (Sharma N et al) and in cis with a delta F508 where another variant in trans was not detected (Hicks K et al). The missense variant c.473G>A (p.S158N) in CFTR (NM_000492.4) is observed in 18/30330 (0.0593%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. The p.S158N missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 158 of CFTR is conserved in all mammalian species. The nucleotide c.473 in CFTR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Since it has been detected in cis with deltaF508 variant in one patient, it's independent pathogenic potential is unclear and hence has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 158 of the CFTR protein (p.Ser158Asn). This variant is present in population databases (rs397508725, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 30760291; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.605G>A. ClinVar contains an entry for this variant (Variation ID: 618959). 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	Ambry Genetics	Feb 10, 2023	The p.S158N variant (also known as c.473G>A and c.605G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 473. The serine at codon 158 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported along with p.F508del in the compound heterozygous state in an individual with chronic cough, sweat chloride level of 64 mmol/L and pancreatic insufficiency (Sharma N et al. Ann Hum Genet, 2009 Jan;73:26-33). This amino acid position is highly 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. -

CFTR-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 24, 2023	The CFTR c.473G>A variant is predicted to result in the amino acid substitution p.Ser158Asn. This variant has been reported in the compound heterozygous state in an individual with cystic fibrosis and in the homozygous state in an individual with failure to thrive, delayed growth, muscle weakness, dehydration and polyuria (Sharma N et al 2008. PubMed ID: 18782298; Najafi M et al 2019. PubMed ID: 30760291). This variant has been reported in cis with the p.Phe508del pathogenic variant in an unaffected sibling of an individual with cystic fibrosis, in whom a second variant was not found (Hicks K et al 2003. PubMed ID: 12820707). This variant has also been reported in the heterozygous state in an individual with chronic pancreatitis ( Supplementary Table 1, Midha S et al 2010. PubMed ID: 20551465). This variant is not present in the CFTR2 database and to our knowledge, no functional studies are available in the literature. This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117171152-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 24, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 25, 2024

Variant summary: CFTR c.473G>A (p.Ser158Asn) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249072 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (7.2e-05 vs 0.013), allowing no conclusion about variant significance. c.473G>A has been reported in the literature in individuals affected with Cystic Fibrosis, including at least one compound heterozygous and one homozygous occurrence (e.g. Hicks_2003, Sharma_2009, Najafi_2019, da Silva Filho_2021, Zampoli_2021, Vaidyanathan_2022). However, the variant has also been reported to co-occur in cis with a known pathogenic variant in a CF patient (Hicks_2003). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 12.97% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 12820707, 20551465, 24440239, 30760291, 18782298, 35857025, 34350279, 32819855, 38388235). ClinVar contains an entry for this variant (Variation ID: 618959). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense c.473G>A (p.Ser158Asn) variant in the CFTR gene has been observed in individual(s) with clinical features of cystic fibrosis (Najafi, Maryam et al., 2019). The variant has been reported previously in both trans (Sharma N et al, 2009) and in cis with a delta F508 where another variant in trans was not detected (Hicks K et al, 2003). This variant is reported with the allele frequency (0.007%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Uncertain Significance (multiple submissions). The amino acid Serine at position 158 is changed to a Asparagine changing protein sequence and it might alter its composition and physico-chemical properties. The serine residue at codon 158 of CFTR is conserved in all mammalian species. The amino acid change p.Ser158Asn in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. Since it has been detected in cis with deltaF508 variant in one patient, it's independent pathogenic potential is unclear and hence has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;T;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.66

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.7

M;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.6

N;.;.;N;.

REVEL

Pathogenic

0.65

Sift

Benign

0.078

T;.;.;T;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.83

MutPred

0.67

Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);Gain of MoRF binding (P = 0.1268);

MVP

1.0

MPC

0.014

ClinPred

0.45

GERP RS

5.7

Varity_R

0.84

gMVP

0.95

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