rs4975646

Variant names:

• chr5-1433286-G-A
• rs4975646
• NM_001044.5:c.419-588C>T

Variant summary

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

The NM_001044.5(SLC6A3):​c.419-588C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 151,784 control chromosomes in the GnomAD database, including 5,458 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 0.24 (5458 hom., cov: 32)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 16 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044.5. 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.419-588C>T		intron	N/A	NP_001035.1	Q01959

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	ENST00000270349.12	TSL:1 MANE Select	c.419-588C>T		intron	N/A	ENSP00000270349.9	Q01959
	SLC6A3	ENST00000941790.1		c.419-588C>T		intron	N/A	ENSP00000611849.1
	SLC6A3	ENST00000713696.1		c.419-588C>T		intron	N/A	ENSP00000519000.1	A0AAQ5BGN6

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35869 AN: 151666 Hom.: 5459 Cov.: 32

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.00892

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.262

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.236 AC: 35855 AN: 151784 Hom.: 5458 Cov.: 32 AF XY: 0.232 AC XY: 17208 AN XY: 74172

African (AFR) AF: 0.0683 AC: 2830 AN: 41414

American (AMR) AF: 0.218 AC: 3332 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3468

East Asian (EAS) AF: 0.00894 AC: 46 AN: 5144

South Asian (SAS) AF: 0.207 AC: 994 AN: 4800

European-Finnish (FIN) AF: 0.275 AC: 2898 AN: 10554

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23734 AN: 67828

Other (OTH) AF: 0.257 AC: 542 AN: 2106

Alfa AF: 0.323 Hom.: 7296

Bravo AF: 0.225

Asia WGS AF: 0.114 AC: 398 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.15
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: rs4975646; hg19: chr5-1433401; COSMIC: COSV54366784;