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), Ambry Genetics, PanelApp Australia, Orphanet

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 VariationId is 55963.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000111.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A3	NM_000111.3	MANE Select	c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC	p.Phe344_Val349delinsAspAla	missense conservative_inframe_deletion	N/A	NP_000102.1	P40879

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A3	ENST00000340010.10	TSL:1 MANE Select	c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC	p.Phe344_Val349delinsAspAla	missense conservative_inframe_deletion	N/A	ENSP00000345873.5	P40879
	SLC26A3	ENST00000852261.1		c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC	p.Phe344_Val349delinsAspAla	missense conservative_inframe_deletion	N/A	ENSP00000522320.1
	SLC26A3	ENST00000852262.1		c.1030_1047delTTCGGCATCGCAATGGTTinsGATGCC	p.Phe344_Val349delinsAspAla	missense conservative_inframe_deletion	N/A	ENSP00000522321.1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital secretory diarrhea, chloride type (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs386833445;

hg19: chr7-107423722;