chr5-477346-AG-A

Variant names:

• chr5-477346-AG-A
• rs869320692
• NM_004174.4:c.1745delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004174.4(SLC9A3):​c.1745delC​(p.Ser582LeufsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC9A3 NM_004174.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.10
• Publications: 1 publications found

Genes affected

SLC9A3 (HGNC:11073): (solute carrier family 9 member A3) The protein encoded by this gene is an epithelial brush border Na/H exchanger that uses an inward sodium ion gradient to expel acids from the cell. Defects in this gene are a cause of congenital secretory sodium diarrhea. Pseudogenes of this gene exist on chromosomes 10 and 22. [provided by RefSeq, Mar 2016]

SLC9A3-AS1 (HGNC:40550): (SLC9A3 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 5-477346-AG-A is Pathogenic according to our data. Variant chr5-477346-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224598.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004174.4. 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
	SLC9A3	NM_004174.4	MANE Select	c.1745delC	p.Ser582LeufsTer6	frameshift	Exon 11 of 17	NP_004165.2	P48764-1
	SLC9A3	NM_001284351.3		c.1718delC	p.Ser573LeufsTer6	frameshift	Exon 11 of 17	NP_001271280.1	P48764-2
	SLC9A3-AS1	NR_125375.1		n.772+11delG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A3	ENST00000264938.8	TSL:1 MANE Select	c.1745delC	p.Ser582LeufsTer6	frameshift	Exon 11 of 17	ENSP00000264938.3	P48764-1
	SLC9A3	ENST00000514375.1	TSL:1	c.1718delC	p.Ser573LeufsTer6	frameshift	Exon 11 of 17	ENSP00000422983.1	P48764-2
	SLC9A3	ENST00000644203.1		c.1745delC	p.Ser582LeufsTer6	frameshift	Exon 11 of 16	ENSP00000495903.1	A0A2R8Y780

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital secretory sodium diarrhea 8 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869320692; hg19: chr5-477461;