5-474893-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004174.4(SLC9A3):c.2491T>C(p.Ser831Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,594,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SLC9A3
NM_004174.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

Variant links:

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 links:

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

SLC9A3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2892916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC9A3	NM_004174.4 linkuse as main transcript	c.2491T>C	p.Ser831Pro	missense_variant	16/17	ENST00000264938.8
SLC9A3-AS1	NR_125375.1 linkuse as main transcript	n.165-244A>G		intron_variant, non_coding_transcript_variant
SLC9A3	NM_001284351.3 linkuse as main transcript	c.2464T>C	p.Ser822Pro	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A3	ENST00000264938.8 linkuse as main transcript	c.2491T>C	p.Ser831Pro	missense_variant	16/17	1	NM_004174.4	P2	P48764-1
SLC9A3-AS1	ENST00000607286.5 linkuse as main transcript	n.165-244A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000738

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000973

AC:

AN:

205538

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

112458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000225

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

AN:

1443126

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

716198

show subpopulations

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:

0.0000245

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000331

AC:

AN:

151122

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73782

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000738

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000848

Hom.:

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 29, 2022

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 831 of the SLC9A3 protein (p.Ser831Pro). This variant is present in population databases (rs754007631, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SLC9A3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.054

T;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.52

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.83

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.050

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.098

T;T

Polyphen

0.93

P;.

Vest4

0.47

MutPred

0.065

Loss of phosphorylation at S831 (P = 0.0194);.;

MVP

0.62

MPC

0.71

ClinPred

0.66

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.20

gMVP

0.14

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over