rs386833445

Variant names:

• chr7-107783277-AACCATTGCGATGCCGAA-GGCATC
• rs386833445
• NM_000111.3:c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The NM_000111.3(SLC26A3):​c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC​(p.Phe344_Val349delinsAspAla) variant causes a missense, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F344F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A3 NM_000111.3 missense, conservative_inframe_deletion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.50
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000111.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000111.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-107783277-AACCATTGCGATGCCGAA-GGCATC is Pathogenic according to our data. Variant chr7-107783277-AACCATTGCGATGCCGAA-GGCATC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55963.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A3	NM_000111.3	c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC	p.Phe344_Val349delinsAspAla	missense_variant, conservative_inframe_deletion		ENST00000340010.10	NP_000102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A3	ENST00000340010.10	c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC	p.Phe344_Val349delinsAspAla	missense_variant, conservative_inframe_deletion		1	NM_000111.3	ENSP00000345873.5
SLC26A3	ENST00000379083.7	n.*821_*838delTTCGGCATCGCAATGGTTinsGATGCC		non_coding_transcript_exon_variant	Exon 9 of 20	2		ENSP00000368375.3
SLC26A3	ENST00000468551.1	n.308_325delTTCGGCATCGCAATGGTTinsGATGCC		non_coding_transcript_exon_variant	Exon 3 of 5	2
SLC26A3	ENST00000379083.7	n.*821_*838delTTCGGCATCGCAATGGTTinsGATGCC		3_prime_UTR_variant	Exon 9 of 20	2		ENSP00000368375.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital secretory diarrhea, chloride type Pathogenic:1

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=2/198	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs386833445; hg19: chr7-107423722;