5-474961-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_004174.4(SLC9A3):c.2423G>A(p.Ser808Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000925 in 1,610,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

SLC9A3
NM_004174.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.246

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0042083263).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000427 (65/152074) while in subpopulation AFR AF= 0.00157 (65/41484). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC9A3	NM_004174.4 linkuse as main transcript	c.2423G>A	p.Ser808Asn	missense_variant	16/17	ENST00000264938.8
SLC9A3-AS1	NR_125375.1 linkuse as main transcript	n.165-176C>T		intron_variant, non_coding_transcript_variant
SLC9A3	NM_001284351.3 linkuse as main transcript	c.2396G>A	p.Ser799Asn	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A3	ENST00000264938.8 linkuse as main transcript	c.2423G>A	p.Ser808Asn	missense_variant	16/17	1	NM_004174.4	P2	P48764-1
SLC9A3-AS1	ENST00000607286.5 linkuse as main transcript	n.165-176C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

239146

Hom.:

AF XY:

0.0000843

AC XY:

AN XY:

130484

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.0000296

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000576

AC:

AN:

1458100

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725234

show subpopulations

Gnomad4 AFR exome

AF:

0.00236

Gnomad4 AMR exome

AF:

0.0000451

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:

0.00

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.000427

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00157

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000156

Hom.:

Bravo

AF:

0.000502

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

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

Mar 01, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 808 of the SLC9A3 protein (p.Ser808Asn). This variant is present in population databases (rs201053062, gnomAD 0.2%). 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.038

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.37

N;N

REVEL

Benign

0.13

Sift

Benign

0.60

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;.

Vest4

0.049

MVP

0.19

MPC

0.23

ClinPred

0.016

GERP RS

-9.6

Varity_R

0.075

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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