Genetic Variant SLC6A15:p.Met722Thr (chr12-84861660-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_182767.6(SLC6A15):c.2165T>C(p.Met722Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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: 0.347

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06775552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A15	NM_182767.6 link	c.2165T>C	p.Met722Thr	missense_variant	Exon 12 of 12	ENST00000266682.10	NP_877499.1	Q9H2J7-1
SLC6A15	NM_001146335.3 link	c.1844T>C	p.Met615Thr	missense_variant	Exon 11 of 11		NP_001139807.1	Q9H2J7-3Q9NW50Q8IXG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A15	ENST00000266682.10 link	c.2165T>C	p.Met722Thr	missense_variant	Exon 12 of 12	1	NM_182767.6	ENSP00000266682.5		Q9H2J7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452150

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33204

American (AMR)

AF:

0.00

AC:

AN:

44120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25772

East Asian (EAS)

AF:

0.00

AC:

AN:

39478

South Asian (SAS)

AF:

0.00

AC:

AN:

85840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104914

Other (OTH)

AF:

0.00

AC:

AN:

59878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2165T>C (p.M722T) alteration is located in exon 12 (coding exon 11) of the SLC6A15 gene. This alteration results from a T to C substitution at nucleotide position 2165, causing the methionine (M) at amino acid position 722 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

0.18

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.038

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.64

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.7

L;.

PhyloP100

0.35

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.11

Sift

Benign

0.96

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.26

B;.

Vest4

0.29

MutPred

0.25

Gain of catalytic residue at P723 (P = 0.0032);.;

MVP

0.47

MPC

0.35

ClinPred

0.079

GERP RS

0.43

Varity_R

0.18

gMVP

0.64

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over