7-117531098-G-A

Variant names:

• chr7-117531098-G-A
• rs397508725
• NM_000492.4:c.473G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP5

The NM_000492.4(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 NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:8
• Conservation: PhyloP100: 9.52
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• 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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.473G>A	p.Ser158Asn	missense_variant	Exon 4 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.473G>A	p.Ser158Asn	missense_variant	Exon 4 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000723 AC: 18 AN: 249072 AF XY: 0.000111

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460566 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 726530

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000476 AC: 41 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111348

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:5

Oct 18, 2022

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 05, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 06, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 five 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, Varkki_2024, Labcorp (formerly Invitae)). 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). This variant is also known as c.605G>A. The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 12820707, 20551465, 24440239, 30760291, 18782298, 35857025, 38966678, 34350279, 32819855). ClinVar contains an entry for this variant (Variation ID: 618959). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Variant of Uncertain Significance (VUS). -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Uncertain:2

Dec 04, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Jan 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;T;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.7	M;.;.;.;M
PhyloP100		9.5
PrimateAI	Uncertain	0.76	T
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	T
GERP RS		5.7
Varity_R		0.84
gMVP		0.95
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs397508725; hg19: chr7-117171152;