rs121913032

Positions:

• chr7-107791059-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 6.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 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. Variant chr7-107791059-C-A is described in Lovd as [Likely_pathogenic]. Variant chr7-107791059-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A3	NM_000111.3	c.559G>T	p.Gly187*	stop_gained	5/21	ENST00000340010.10	NP_000102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A3	ENST00000340010.10	c.559G>T	p.Gly187*	stop_gained	5/21	1	NM_000111.3	ENSP00000345873.5
SLC26A3	ENST00000379083.7	n.*350G>T		non_coding_transcript_exon_variant	5/20	2		ENSP00000368375.3
SLC26A3	ENST00000379083.7	n.*350G>T		3_prime_UTR_variant	5/20	2		ENSP00000368375.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461540 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727060

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital secretory diarrhea, chloride type Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	literature only	Genetics Research Lab, Taif University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PVS1, PM3_VeryStrong, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 2023	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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16759). This premature translational stop signal has been observed in individual(s) with congenital chloride diarrhea (PMID: 9718329, 23361499, 25568271, 27525615). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.79
GERP RS		5.7

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

LitVar

Other links and lift over

dbSNP: rs121913032; hg19: chr7-107431504;