rs869312806

Variant names:

• chr5-484520-G-A
• rs869312806
• NM_004174.4:c.932C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004174.4(SLC9A3):​c.932C>T​(p.Ala311Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC9A3 NM_004174.4 missense, splice_region
• Scores: Splicing: ADA: 0.6084
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-484520-G-A is Pathogenic according to our data. Variant chr5-484520-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 224595.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A3	NM_004174.4	c.932C>T	p.Ala311Val	missense_variant, splice_region_variant	Exon 5 of 17	ENST00000264938.8	NP_004165.2
SLC9A3	NM_001284351.3	c.932C>T	p.Ala311Val	missense_variant, splice_region_variant	Exon 5 of 17		NP_001271280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A3	ENST00000264938.8	c.932C>T	p.Ala311Val	missense_variant, splice_region_variant	Exon 5 of 17	1	NM_004174.4	ENSP00000264938.3
SLC9A3	ENST00000514375.1	c.932C>T	p.Ala311Val	missense_variant, splice_region_variant	Exon 5 of 17	1		ENSP00000422983.1
SLC9A3	ENST00000644203.1	c.932C>T	p.Ala311Val	missense_variant, splice_region_variant	Exon 5 of 16			ENSP00000495903.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460510 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726598

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital secretory sodium diarrhea 8 Pathogenic:1

Oct 06, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	.;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.4	.;M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.4	.;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.0040	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.95
MVP		0.65
MPC		2.0
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.030		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: rs869312806; hg19: chr5-484635;