ENST00000512002.2:n.479G>A

Variant names:

• chr5-1394500-C-T
• rs28363167
• ENST00000512002.2:n.479G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000512002.2(SLC6A3):​n.479G>A 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 0.00293 in 634,504 control chromosomes in the GnomAD database, including 25 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 0.0087 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: SLC6A3 ENST00000512002.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.941
• Publications: 6 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=-0.77).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00866 (1318/152278) while in subpopulation AFR AF = 0.0295 (1224/41546). AF 95% confidence interval is 0.0281. There are 20 homozygotes in GnomAd4. There are 606 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.*235G>A		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.479G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
SLC6A3	ENST00000270349.12	c.*235G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.*293G>A		3_prime_UTR_variant	Exon 15 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.00864 AC: 1315 AN: 152160 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00113 AC: 544 AN: 482226 Hom.: 5 Cov.: 3 AF XY: 0.000949 AC XY: 243 AN XY: 256140

African (AFR) AF: 0.0291 AC: 399 AN: 13692

American (AMR) AF: 0.00197 AC: 55 AN: 27944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15506

East Asian (EAS) AF: 0.00 AC: 0 AN: 31358

South Asian (SAS) AF: 0.000199 AC: 10 AN: 50352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30508

Middle Eastern (MID) AF: 0.00153 AC: 5 AN: 3270

European-Non Finnish (NFE) AF: 0.0000603 AC: 17 AN: 282108

Other (OTH) AF: 0.00211 AC: 58 AN: 27488

GnomAD4 genome AF: 0.00866 AC: 1318 AN: 152278 Hom.: 20 Cov.: 33 AF XY: 0.00814 AC XY: 606 AN XY: 74454

African (AFR) AF: 0.0295 AC: 1224 AN: 41546

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00573 Hom.: 4

Bravo AF: 0.00992

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 17, 2018

GeneDx

Significance: Likely 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	-0.77
CADD	Benign	7.2
DANN	Benign	0.83
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism

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: rs28363167; hg19: chr5-1394615;