Genetic Variant SLC6A3:c.1270-21G>A (chr5-1409870-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001044.5(SLC6A3):c.1270-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,612,242 control chromosomes in the GnomAD database, including 27,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.15 ( 1920 hom., cov: 33)

Exomes 𝑓: 0.18 ( 25886 hom. )

Consequence

SLC6A3
NM_001044.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.05

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 5-1409870-C-T is Benign according to our data. Variant chr5-1409870-C-T is described in ClinVar as [Benign]. Clinvar id is 1180099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5 link	c.1270-21G>A		intron_variant	Intron 9 of 14	ENST00000270349.12	NP_001035.1	Q01959

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12 link	c.1270-21G>A		intron_variant	Intron 9 of 14	1	NM_001044.5	ENSP00000270349.9		Q01959

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22541

AN:

152120

Hom.:

1922

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.167

Gnomad EAS

AF:

0.0782

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.197

Gnomad NFE

AF:

0.202

Gnomad OTH

AF:

0.169

GnomAD3 exomes

AF:

0.155

AC:

38581

AN:

249542

Hom.:

3460

AF XY:

0.158

AC XY:

21435

AN XY:

135296

show subpopulations

Gnomad AFR exome

AF:

0.0695

Gnomad AMR exome

AF:

0.0991

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.0713

Gnomad SAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.202

Gnomad OTH exome

AF:

0.187

GnomAD4 exome

AF:

0.183

AC:

267607

AN:

1460004

Hom.:

25886

Cov.:

AF XY:

0.183

AC XY:

132685

AN XY:

726278

show subpopulations

Gnomad4 AFR exome

AF:

0.0701

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.178

Gnomad4 EAS exome

AF:

0.0560

Gnomad4 SAS exome

AF:

0.125

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.200

Gnomad4 OTH exome

AF:

0.179

GnomAD4 genome

AF:

0.148

AC:

22542

AN:

152238

Hom.:

1920

Cov.:

AF XY:

0.145

AC XY:

10819

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0720

Gnomad4 AMR

AF:

0.131

Gnomad4 ASJ

AF:

0.167

Gnomad4 EAS

AF:

0.0776

Gnomad4 SAS

AF:

0.128

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.202

Gnomad4 OTH

AF:

0.166

Alfa

AF:

0.152

Hom.:

625

Bravo

AF:

0.143

Asia WGS

AF:

0.0910

AC:

318

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.8

DANN

Benign

0.41

BranchPoint Hunter

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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