dbSNP rs869312807: SLC9A3:p.Ala269Thr (chr5-484647-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_004174.4(SLC9A3):c.805G>A(p.Ala269Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC9A3
NM_004174.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.808

PP5

Variant 5-484647-C-T is Pathogenic according to our data. Variant chr5-484647-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 224599.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A3	NM_004174.4 link	c.805G>A	p.Ala269Thr	missense_variant	Exon 5 of 17	ENST00000264938.8	NP_004165.2	P48764-1
SLC9A3	NM_001284351.3 link	c.805G>A	p.Ala269Thr	missense_variant	Exon 5 of 17		NP_001271280.1	P48764-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC9A3	ENST00000264938.8 link	c.805G>A	p.Ala269Thr	missense_variant	Exon 5 of 17	1	NM_004174.4	ENSP00000264938.3	P48764-1
SLC9A3	ENST00000514375.1 link	c.805G>A	p.Ala269Thr	missense_variant	Exon 5 of 17	1		ENSP00000422983.1	P48764-2
SLC9A3	ENST00000644203.1 link	c.805G>A	p.Ala269Thr	missense_variant	Exon 5 of 16			ENSP00000495903.1	A0A2R8Y780

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726734

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

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

- -

not provided

Pathogenic:1

Oct 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

.;T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.7

.;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0030

.;D;D

Sift4G

Uncertain

0.011

.;D;D

Polyphen

1.0

.;D;.

Vest4

0.91, 0.86

MutPred

0.71

Gain of MoRF binding (P = 0.1637);Gain of MoRF binding (P = 0.1637);Gain of MoRF binding (P = 0.1637);

MVP

0.56

MPC

2.0

ClinPred

0.99

GERP RS

4.5

Varity_R

0.51

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

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

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