rs869312806

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A311T) has been classified as Likely benign.

• 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
• Publications: 5 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 Gene-Disease associations (from GenCC):

• congenital secretory sodium diarrhea 8

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital sodium diarrhea

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		9.6
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
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869312806; hg19: chr5-484635;