Genetic Variant NM_001044.5:c.-199T>A (chr5-1445501-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001044.5(SLC6A3):c.-199T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 172,712 control chromosomes in the GnomAD database, including 23,549 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.50 ( 19864 hom., cov: 32)

Exomes 𝑓: 0.55 ( 3685 hom. )

Consequence

SLC6A3
NM_001044.5 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

Publications

41 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5 link	c.-199T>A		upstream_gene_variant		ENST00000270349.12	NP_001035.1	Q01959

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SLC6A3	ENST00000270349.12 link	c.-199T>A	upstream_gene_variant	1	NM_001044.5	ENSP00000270349.9	Q01959
SLC6A3	ENST00000713696.1 link	c.-199T>A	upstream_gene_variant			ENSP00000519000.1
SLC6A3	ENST00000713698.1 link	c.-199T>A	upstream_gene_variant			ENSP00000519002.1
SLC6A3	ENST00000713697.1 link	n.-199T>A	upstream_gene_variant			ENSP00000519001.1

Frequencies

GnomAD3 genomes

AF:

0.502

AC:

75474

AN:

150414

Hom.:

19846

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.584

Gnomad AMR

AF:

0.480

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.171

Gnomad SAS

AF:

0.469

Gnomad FIN

AF:

0.565

Gnomad MID

AF:

0.568

Gnomad NFE

AF:

0.596

Gnomad OTH

AF:

0.514

GnomAD4 exome

AF:

0.549

AC:

12175

AN:

22176

Hom.:

3685

AF XY:

0.549

AC XY:

6533

AN XY:

11900

show subpopulations

African (AFR)

AF:

0.370

AC:

151

AN:

408

American (AMR)

AF:

0.430

AC:

184

AN:

428

Ashkenazi Jewish (ASJ)

AF:

0.645

AC:

355

AN:

550

East Asian (EAS)

AF:

0.121

AC:

219

AN:

1814

South Asian (SAS)

AF:

0.454

AC:

AN:

194

European-Finnish (FIN)

AF:

0.587

AC:

1978

AN:

3368

Middle Eastern (MID)

AF:

0.508

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.603

AC:

8550

AN:

14168

Other (OTH)

AF:

0.523

AC:

589

AN:

1126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

246

491

737

982

1228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.502

AC:

75537

AN:

150536

Hom.:

19864

Cov.:

AF XY:

0.500

AC XY:

36794

AN XY:

73568

show subpopulations

African (AFR)

AF:

0.371

AC:

15161

AN:

40906

American (AMR)

AF:

0.480

AC:

7295

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2073

AN:

3456

East Asian (EAS)

AF:

0.171

AC:

837

AN:

4882

South Asian (SAS)

AF:

0.471

AC:

2240

AN:

4756

European-Finnish (FIN)

AF:

0.565

AC:

5891

AN:

10432

Middle Eastern (MID)

AF:

0.569

AC:

164

AN:

288

European-Non Finnish (NFE)

AF:

0.596

AC:

40261

AN:

67600

Other (OTH)

AF:

0.517

AC:

1084

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

1943

3886

5829

7772

9715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.537

Hom.:

2798

Bravo

AF:

0.482

Asia WGS

AF:

0.334

AC:

1152

AN:

3442

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.30

PhyloP100

-1.2

PromoterAI

-0.16

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over