rs386833491

chr7-107786844-AACC-Achr7-107786844-AACC-AACCACC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000111.3(SLC26A3):c.951_953del(p.Val318del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: SLC26A3 NM_000111.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 7.48

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 63) in uniprot entity S26A3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000111.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000111.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-107786844-AACC-A is Pathogenic according to our data. Variant chr7-107786844-AACC-A is described in ClinVar as [Pathogenic]. Clinvar id is 16754.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107786844-AACC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A3	NM_000111.3	c.951_953del	p.Val318del	inframe_deletion	8/21	ENST00000340010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A3	ENST00000340010.10	c.951_953del	p.Val318del	inframe_deletion	8/21	1	NM_000111.3	P1
SLC26A3	ENST00000468551.1	n.229_231del		non_coding_transcript_exon_variant	2/5	2
SLC26A3	ENST00000379083.7	c.*742_*744del		3_prime_UTR_variant, NMD_transcript_variant	8/20	2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152174 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: 0.00

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000473 AC: 119 AN: 251340 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135850

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: 0.00

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000187 AC: 273 AN: 1461664 Hom.: 0 AF XY: 0.000166 AC XY: 121 AN XY: 727158

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: 0.00491

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74484

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: 0.00527

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital secretory diarrhea, chloride type Pathogenic:3

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000111.2:c.951_953delGGT in the SLC26A3 gene has an allele frequency of 0.005 in European (Finnish) subpopulation in the gnomAD database. The SLC26A3 c.951_953delGGT (p.Val318del) variant has been reported as a Finnish founder mutation, which has been detected in 45 patients (PMID: 21394828). The mouse p.V318del-homologue mutant (p.V310del) is retained in the endoplasmic reticulum, failing to show any expression on the apical plasma membrane (PMID: 21394828). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM4; PS3. -
Pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2023

This variant has been observed in individual(s) with congenital secretory chloride diarrhea (PMID: 8896562, 21394828). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs386833491, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This variant, c.951_953del, results in the deletion of 1 amino acid(s) of the SLC26A3 protein (p.Val318del), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 16754). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC26A3 function (PMID: 9886994). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386833491; hg19: chr7-107427289;