5-1394407-C-T

Variant names:

• chr5-1394407-C-T
• rs27072
• ENST00000512002.2:n.572G>A

Variant summary

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

The ENST00000512002.2(SLC6A3):​n.572G>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 0.187 in 494,750 control chromosomes in the GnomAD database, including 9,367 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 0.18 (2492 hom., cov: 32)
  • Exomes 𝑓: 0.19 (6875 hom.)
• Consequence: SLC6A3 ENST00000512002.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.06
• Publications: 106 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.*328G>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.572G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
SLC6A3	ENST00000270349.12	c.*328G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.*386G>A		3_prime_UTR_variant	Exon 15 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26786 AN: 151990 Hom.: 2488 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.192 AC: 65849 AN: 342642 Hom.: 6875 Cov.: 0 AF XY: 0.197 AC XY: 35422 AN XY: 179792

African (AFR) AF: 0.136 AC: 1367 AN: 10038

American (AMR) AF: 0.226 AC: 3346 AN: 14812

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 1856 AN: 10542

East Asian (EAS) AF: 0.221 AC: 5063 AN: 22890

South Asian (SAS) AF: 0.259 AC: 10218 AN: 39472

European-Finnish (FIN) AF: 0.193 AC: 3750 AN: 19464

Middle Eastern (MID) AF: 0.202 AC: 307 AN: 1518

European-Non Finnish (NFE) AF: 0.178 AC: 36272 AN: 204230

Other (OTH) AF: 0.187 AC: 3670 AN: 19676

GnomAD4 genome AF: 0.176 AC: 26810 AN: 152108 Hom.: 2492 Cov.: 32 AF XY: 0.179 AC XY: 13329 AN XY: 74348

African (AFR) AF: 0.139 AC: 5759 AN: 41484

American (AMR) AF: 0.216 AC: 3309 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3468

East Asian (EAS) AF: 0.252 AC: 1304 AN: 5172

South Asian (SAS) AF: 0.260 AC: 1251 AN: 4820

European-Finnish (FIN) AF: 0.193 AC: 2042 AN: 10572

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.177 AC: 12037 AN: 67978

Other (OTH) AF: 0.168 AC: 356 AN: 2114

Alfa AF: 0.174 Hom.: 8540

Bravo AF: 0.173

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21525861) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.42
PhyloP100		-2.1
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: rs27072; hg19: chr5-1394522;