5-1394700-A-G

Variant names:

• chr5-1394700-A-G
• rs1042098
• ENST00000512002.2:n.279T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000512002.2(SLC6A3):​n.279T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,607,322 control chromosomes in the GnomAD database, including 58,493 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 0.31 (7814 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50679 hom.)
• Consequence: SLC6A3 ENST00000512002.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.652
• Publications: 33 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.*35T>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000512002.2	n.279T>C		non_coding_transcript_exon_variant	Exon 3 of 3	1
SLC6A3	ENST00000270349.12	c.*35T>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.*93T>C		3_prime_UTR_variant	Exon 15 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46431 AN: 152022 Hom.: 7795 Cov.: 33

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.312

GnomAD2 exomes AF: 0.249 AC: 62568 AN: 251402 AF XY: 0.250

Gnomad AFR exome AF: 0.460

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.0967

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.257 AC: 373267 AN: 1455182 Hom.: 50679 Cov.: 29 AF XY: 0.256 AC XY: 185585 AN XY: 724410

African (AFR) AF: 0.464 AC: 15462 AN: 33302

American (AMR) AF: 0.178 AC: 7971 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10840 AN: 26078

East Asian (EAS) AF: 0.0880 AC: 3492 AN: 39666

South Asian (SAS) AF: 0.228 AC: 19612 AN: 86124

European-Finnish (FIN) AF: 0.196 AC: 10461 AN: 53336

Middle Eastern (MID) AF: 0.368 AC: 2120 AN: 5754

European-Non Finnish (NFE) AF: 0.259 AC: 286285 AN: 1106008

Other (OTH) AF: 0.283 AC: 17024 AN: 60206

GnomAD4 genome AF: 0.306 AC: 46499 AN: 152140 Hom.: 7814 Cov.: 33 AF XY: 0.299 AC XY: 22241 AN XY: 74380

African (AFR) AF: 0.453 AC: 18771 AN: 41468

American (AMR) AF: 0.243 AC: 3712 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1436 AN: 3470

East Asian (EAS) AF: 0.101 AC: 520 AN: 5166

South Asian (SAS) AF: 0.236 AC: 1140 AN: 4830

European-Finnish (FIN) AF: 0.189 AC: 2005 AN: 10604

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17939 AN: 67982

Other (OTH) AF: 0.309 AC: 653 AN: 2112

Alfa AF: 0.282 Hom.: 17792

Bravo AF: 0.317

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Classic dopamine transporter deficiency syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

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	-0.89
CADD	Benign	2.2
DANN	Benign	0.34
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042098; hg19: chr5-1394815; COSMIC: COSV54361722;