Genetic Variant SLC6A3:p.Thr613Lys (chr5-1400916-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001044.5(SLC6A3):c.1838C>A(p.Thr613Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,429,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T613M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

SLC6A3
NM_001044.5 missense, splice_region

Scores

Splicing: ADA: 0.007521

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

2 publications found

Variant links:

Genes affected

SLC6A3 (HGNC:11049): (solute carrier family 6 member 3) This gene encodes a dopamine transporter which is a member of the sodium- and chloride-dependent neurotransmitter transporter family. The 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 11 copies. Variation in the number of repeats is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence.[provided by RefSeq, Nov 2009]

SLC6A3 Gene-Disease associations (from GenCC):

classic dopamine transporter deficiency syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
SLC6A3-related dopamine transporter deficiency syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
parkinsonism-dystonia, infantile
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC6A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.114593565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5 link	c.1838C>A	p.Thr613Lys	missense_variant, splice_region_variant	Exon 14 of 15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC6A3	ENST00000270349.12 link	c.1838C>A	p.Thr613Lys	missense_variant, splice_region_variant	Exon 14 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000512002.2 link	n.219C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	1
SLC6A3	ENST00000713696.1 link	c.*33C>A		splice_region_variant	Exon 14 of 15			ENSP00000519000.1
SLC6A3	ENST00000713696.1 link	c.*33C>A		3_prime_UTR_variant	Exon 14 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000839

AC:

AN:

1429568

Hom.:

Cov.:

AF XY:

0.00000988

AC XY:

AN XY:

708338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32778

American (AMR)

AF:

0.00

AC:

AN:

41604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25584

East Asian (EAS)

AF:

0.00

AC:

AN:

38284

South Asian (SAS)

AF:

0.00

AC:

AN:

82420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

1093046

Other (OTH)

AF:

0.00

AC:

AN:

58978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.76

M_CAP

Benign

0.026

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

PhyloP100

2.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.76

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

0.91

Vest4

0.28

ClinPred

0.25

GERP RS

3.3

Varity_R

0.068

gMVP

0.82

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0075

dbscSNV1_RF

Benign

0.21

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

Computational scores

Splicing

Publications

Other links and lift over