rs121913032

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000111.3(SLC26A3):c.559G>T(p.Gly187*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,540 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC26A3
NM_000111.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 6.90

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

congenital secretory chloride diarrhea 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics

SLC26A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-107791059-C-A is Pathogenic according to our data. Variant chr7-107791059-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 16759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A3	NM_000111.3 link	c.559G>T	p.Gly187*	stop_gained	Exon 5 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.559G>T	p.Gly187*	stop_gained	Exon 5 of 21	1	NM_000111.3	ENSP00000345873.5	P40879
SLC26A3	ENST00000379083.7 link	n.*350G>T		non_coding_transcript_exon_variant	Exon 5 of 20	2		ENSP00000368375.3	F8WBL6
SLC26A3	ENST00000379083.7 link	n.*350G>T		3_prime_UTR_variant	Exon 5 of 20	2		ENSP00000368375.3	F8WBL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital secretory diarrhea, chloride type

Pathogenic:11

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 06, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Sep 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 26, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gly187X variant in SLC26A3 has been reported in at least 35 individuals wi th congenital chloride diarrhea and is a founder pathogenic variant in the Arabi c population (Azzabi 2016, Canani 2013, Abou Ziki 2015, Hoglund 1998, Gutierrez Junquera 2008, Gurakan 2011, Al Awadhi 2017, Amato 2017). This variant was absen t from large population studies; however, these studies do not include Arab popu lations. This variant has been reported in ClinVar (Variation ID # 16759). This nonsense variant leads to a premature termination codon at position 187 which is predicted to lead to a truncated or absent protein. Loss of function of the SLC 26A3 gene is an established disease mechanism in autosomal recessive congenital chloride diarrhea. In summary, this variant meets criteria to be classified as p athogenic for congenital chloride diarrhea in an autosomal recessive manner base d upon proband counts and predicted impact on protein. ACMG/AMP Criteria applied : PVS1, PM3_Strong. -

Jan 29, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 10, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetics Research Lab, Taif University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1, PM3_VeryStrong, PM2 -

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000016759, PMID:9718329). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Jan 07, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25568271, 25525159, 28600779, 21853658, 33350492, 27525615, 29086717, 9718329, 31130284, 33567694, 23361499) -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gly187*) in the SLC26A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A3 are known to be pathogenic (PMID: 9718329, 21394828). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital chloride diarrhea (PMID: 9718329, 23361499, 25568271, 27525615). ClinVar contains an entry for this variant (Variation ID: 16759). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

PhyloP100

6.9

Vest4

0.79

GERP RS

5.7

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs121913032

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over