rs28364997

Positions:

chr5-1403013-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001044.5(SLC6A3):c.1676C>T(p.Ala559Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

SLC6A3
NM_001044.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.526

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10948989).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000571 (87/152334) while in subpopulation NFE AF= 0.00106 (72/68026). AF 95% confidence interval is 0.000861. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A3	NM_001044.5 linkuse as main transcript	c.1676C>T	p.Ala559Val	missense_variant	13/15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12 linkuse as main transcript	c.1676C>T	p.Ala559Val	missense_variant	13/15	1	NM_001044.5	ENSP00000270349	P1

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000530

AC:

133

AN:

250852

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00130

AC:

1893

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

848

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00164

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000571

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000993

Hom.:

Bravo

AF:

0.000620

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	Reported as an apparently de novo variant in heterozygous state in male patient with global developmental delay, hypotonia, status epilepticus, and lactic acidosis; however, a second SLC6A3 variant was not identified and additional variants in other genes that may have been responsible for the phenotype were also identified in this patient (PMID: 26931468); Reported in heterozygous state in an individual with bipolar disorder; however, a second SLC6A3 variant was not identified and variant did not segregate with other affected family members (PMID: 10889530); Reported in heterozygous state in two siblings with attention deficit hyperactivity disorder; however, additional clinical information and segregation information was not provided (PMID: 16171832); Reported in heterozygous state in two unrelated patients with autism in published literature; however, the variant was maternally inherited in both cases from unaffected mothers (PMID: 25313507); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18614672, 25331903, 20427663, 29559554, 16103889, 16171832, 19590515, 31133547, 34426522, 35317228, 32473160, 33310157, 37238676, 31094705, 37205452, 34000340, 36630507, 34002696, 34104969, 36552823, 36750796, 10889530, 25313507, 38168036, 37987120, 26931468) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2022

The c.1676C>T (p.A559V) alteration is located in exon 13 (coding exon 12) of the SLC6A3 gene. This alteration results from a C to T substitution at nucleotide position 1676, causing the alanine (A) at amino acid position 559 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Classic dopamine transporter deficiency syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Jun 25, 2020

- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 19, 2020

- -

Parkinsonism-dystonia, infantile

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 559 of the SLC6A3 protein (p.Ala559Val). This variant is present in population databases (rs28364997, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with bipolar disorder, attention-deficit hyperactivity disorder (ADHD), speech disfluency, infantile encephalopathy, and/or autism-spectrum disorder (ASD) (PMID: 10889530, 16171832, 19590515, 25313507, 26931468). ClinVar contains an entry for this variant (Variation ID: 290889). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC6A3 function (PMID: 18614672, 20427663, 25313507, 25331903). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.25

CADD

Benign

9.0

DANN

Benign

0.81

DEOGEN2

Benign

0.16

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.75

M_CAP

Benign

0.076

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0050

MutationTaster

Benign

0.95

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.31

REVEL

Uncertain

0.43

Sift

Benign

0.70

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.65

MVP

0.99

MPC

0.60

ClinPred

0.0098

GERP RS

-1.3

Varity_R

0.068

gMVP

0.50

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