Genetic Variant SLC10A3:p.Met249Ile (chrX-154488194-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_019848.5(SLC10A3):c.747G>A(p.Met249Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,210,084 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000015 ( 0 hom. 3 hem. )

Consequence

SLC10A3
NM_019848.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0510

Variant links:

Genes affected

SLC10A3 (HGNC:22979): (solute carrier family 10 member 3) This gene maps to a GC-rich region of the X chromosome and was identified by its proximity to a CpG island. It is thought to be a housekeeping gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Dec 2008]

SLC10A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06256598).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC10A3	NM_019848.5 link	c.747G>A	p.Met249Ile	missense_variant	Exon 2 of 2	ENST00000651600.1	NP_062822.1	P09131-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC10A3	ENST00000651600.1 link	c.747G>A	p.Met249Ile	missense_variant	Exon 2 of 2		NM_019848.5	ENSP00000499188.1		P09131-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112420

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34580

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000934

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:

0.0000874

AC:

AN:

183146

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000547

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:

0.000221

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1097664

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363310

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000483

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:

0.00

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112420

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34580

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000934

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

Bravo

AF:

0.0000453

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.747G>A (p.M249I) alteration is located in exon 2 (coding exon 1) of the SLC10A3 gene. This alteration results from a G to A substitution at nucleotide position 747, causing the methionine (M) at amino acid position 249 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.041

.;T;.;T

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.83

T;T;T;.

M_CAP

Benign

0.069

MetaRNN

Benign

0.063

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.90

.;N;.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.89

N;N;N;N

REVEL

Benign

0.042

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.075

.;B;.;B

Vest4

0.30

MutPred

0.40

.;Gain of catalytic residue at L254 (P = 0.02);.;Gain of catalytic residue at L254 (P = 0.02);

MVP

0.068

MPC

0.61

ClinPred

0.060

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.45

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