NM_000111.3:c.358G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000111.3(SLC26A3):c.358G>A(p.Gly120Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,612,318 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SLC26A3
NM_000111.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.54

Variant links:

Genes affected

SLC26A3 (HGNC:3018): (solute carrier family 26 member 3) The protein encoded by this gene is a transmembrane glycoprotein that transports chloride ions across the cell membrane in exchange for bicarbonate ions. It is localized to the mucosa of the lower intestinal tract, particularly to the apical membrane of columnar epithelium and some goblet cells. The protein is essential for intestinal chloride absorption, and mutations in this gene have been associated with congenital chloride diarrhea. [provided by RefSeq, Oct 2008]

SLC26A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 7-107791854-C-T is Pathogenic according to our data. Variant chr7-107791854-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107791854-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A3	NM_000111.3 link	c.358G>A	p.Gly120Ser	missense_variant	Exon 4 of 21	ENST00000340010.10	NP_000102.1	P40879

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A3	ENST00000340010.10 link	c.358G>A	p.Gly120Ser	missense_variant	Exon 4 of 21	1	NM_000111.3	ENSP00000345873.5	P40879
SLC26A3	ENST00000453332.1 link	c.358G>A	p.Gly120Ser	missense_variant, splice_region_variant	Exon 4 of 4	4		ENSP00000395955.1	C9JFJ2
SLC26A3	ENST00000379083.7 link	n.*149G>A		non_coding_transcript_exon_variant	Exon 4 of 20	2		ENSP00000368375.3	F8WBL6
SLC26A3	ENST00000379083.7 link	n.*149G>A		3_prime_UTR_variant	Exon 4 of 20	2		ENSP00000368375.3	F8WBL6

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151888

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251344

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460430

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726594

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151888

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74180

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:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital secretory diarrhea, chloride type

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.358G>A (p.Gly120Ser) in the SLC26A3 gene has been reported previously in compound heterozygous state in individuals affected with congenital chloride diarrhea (Höglund et al., 2001; Höglund et al., 1998; Wedenoja et al., 2011). This variant is reported with the allele frequency (0.003%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic. The amino acid Gly at position 120 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Leu61Ile in NDP is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid change p.Gly120Ser in SLC26A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 120 of the SLC26A3 protein (p.Gly120Ser). This variant is present in population databases (rs386833479, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital chloride diarrhea (PMID: 9554749, 11524734, 28644346). ClinVar contains an entry for this variant (Variation ID: 55997). 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 SLC26A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

SLC26A3-related disorder

Pathogenic:1

Mar 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC26A3 c.358G>A variant is predicted to result in the amino acid substitution p.Gly120Ser. This variant has been reported in the compound heterozygous states with another SLC26A3 variant in two siblings with congenital chloride diarrhea (CCD) (Swe1.3 and Swe 1.4, Hoglund et al. 1998. PubMed ID: 9554749; Supplemental Table 1, LGL9412 and LGL9413, Hoglund et al. 2001. PubMed ID: 11524734) and in another individual with CDD (Case 4, Esposito et al. 2021. PubMed ID: 33567694). It was reported in the heterozygous state in an individual with CDD and was also present in her unaffected father (I3, Hoglund et al. 1998. PubMed ID: 9554749). This variant was also identified in a study of individuals with congenital chloride diarrhea and other forms of congenial diarrheal diseases, however specific clinical details were not provided (Amato et al. 2017. PubMed ID: 28644346). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;T

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MVP

0.97

MPC

0.70

ClinPred

0.99

GERP RS

5.6

Varity_R

0.91

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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