rs2975226

Variant names:

• chr5-1445501-A-T
• rs2975226
• ENST00000936841.1:c.-199T>A

Variant summary

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

The ENST00000936841.1(SLC6A3):​c.-199T>A variant causes a 5 prime UTR 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 ENST00000936841.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 41 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), G2P, PanelApp Australia, Ambry Genetics
• 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).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000936841.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	NM_001044.5	MANE Select	c.-199T>A		upstream_gene	N/A	NP_001035.1	Q01959

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	ENST00000936841.1		c.-199T>A		5_prime_UTR	Exon 1 of 12	ENSP00000606900.1
	SLC6A3	ENST00000270349.12	TSL:1 MANE Select	c.-199T>A		upstream_gene	N/A	ENSP00000270349.9	Q01959
	SLC6A3	ENST00000941790.1		c.-199T>A		upstream_gene	N/A	ENSP00000611849.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75474 AN: 150414 Hom.: 19846 Cov.: 32

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

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: 88 AN: 194

European-Finnish (FIN) AF: 0.587 AC: 1978 AN: 3368

Middle Eastern (MID) AF: 0.508 AC: 61 AN: 120

European-Non Finnish (NFE) AF: 0.603 AC: 8550 AN: 14168

Other (OTH) AF: 0.523 AC: 589 AN: 1126

GnomAD4 genome AF: 0.502 AC: 75537 AN: 150536 Hom.: 19864 Cov.: 32 AF XY: 0.500 AC XY: 36794 AN XY: 73568

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	10
DANN	Benign	0.30
PhyloP100		-1.2
PromoterAI		-0.16	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2975226; hg19: chr5-1445616;