Genetic Variant SLC6A15:p.Ala455Thr (chr12-84870610-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182767.6(SLC6A15):c.1363G>A(p.Ala455Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC6A15
NM_182767.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.77

Variant links:

Genes affected

SLC6A15 (HGNC:13621): (solute carrier family 6 member 15) This gene encodes a member of the solute carrier family 6 protein family which transports neutral amino acids. The encoded protein is thought to play a role in neuronal amino acid transport (PMID: 16185194) and may be associated with major depression (PMID: 21521612). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

SLC6A15 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A15	NM_182767.6 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 9 of 12	ENST00000266682.10	NP_877499.1	Q9H2J7-1
SLC6A15	NM_001146335.3 link	c.1042G>A	p.Ala348Thr	missense_variant	Exon 8 of 11		NP_001139807.1	Q9H2J7-3Q9NW50Q8IXG2
SLC6A15	XM_011538525.4 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 9 of 10		XP_011536827.1	A0A7P0T8I1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A15	ENST00000266682.10 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 9 of 12	1	NM_182767.6	ENSP00000266682.5		Q9H2J7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249536

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134870

show subpopulations

Gnomad AFR exome

AF:

0.0000619

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1363G>A (p.A455T) alteration is located in exon 9 (coding exon 8) of the SLC6A15 gene. This alteration results from a G to A substitution at nucleotide position 1363, causing the alanine (A) at amino acid position 455 to be replaced by a threonine (T). 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

0.14

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.061

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.4

M;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

N;N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.067

T;T;T

Polyphen

0.98

D;D;.

Vest4

0.70

MVP

0.90

MPC

0.71

ClinPred

0.74

GERP RS

5.6

Varity_R

0.58

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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