chr7-107793742-C-CTT

Variant names:

• chr7-107793742-C-CTT
• rs386833476
• NM_000111.3:c.269_270dupAA

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.269_270dupAA​(p.Gly91LysfsTer3) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000372 in 1,612,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC26A3 NM_000111.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.66

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 7-107793742-C-CTT is Pathogenic according to our data. Variant chr7-107793742-C-CTT is described in ClinVar as [Pathogenic]. Clinvar id is 55994.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	c.269_270dupAA	p.Gly91LysfsTer3	frameshift_variant, splice_region_variant	Exon 3 of 21	ENST00000340010.10	NP_000102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A3	ENST00000340010.10	c.269_270dupAA	p.Gly91LysfsTer3	frameshift_variant, splice_region_variant	Exon 3 of 21	1	NM_000111.3	ENSP00000345873.5
SLC26A3	ENST00000453332.1	c.269_270dupAA	p.Gly91LysfsTer3	frameshift_variant, splice_region_variant	Exon 3 of 4	4		ENSP00000395955.1
SLC26A3	ENST00000379083.7	n.*60_*61dupAA		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 20	2		ENSP00000368375.3
SLC26A3	ENST00000379083.7	n.*60_*61dupAA		3_prime_UTR_variant	Exon 3 of 20	2		ENSP00000368375.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152046 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: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250454 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135414

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460504 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital secretory diarrhea, chloride type Pathogenic:2

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gly91Lysfs*3) 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 present in population databases (rs386833476, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of congenital chloride diarrhea (PMID: 9718329, 31680349, 33191723, 34503561). This variant is also known as c.268–269insAA. ClinVar contains an entry for this variant (Variation ID: 55994). -

Polyhydramnios;C0020305:Hydrops fetalis;C0021843:Intestinal obstruction Pathogenic:1

Oct 16, 2019

Center for Reproductive Medicine, Peking University Third Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833476; hg19: chr7-107434187;