5-1432710-G-T

Variant names:

• chr5-1432710-G-T
• rs460000
• NM_001044.5:c.419-12C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001044.5(SLC6A3):​c.419-12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,605,626 control chromosomes in the GnomAD database, including 57,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8283 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49269 hom.)
• Consequence: SLC6A3 NM_001044.5 intron
• Scores: Splicing: ADA: 0.00003653
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.662
• Publications: 43 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-1432710-G-T is Benign according to our data. Variant chr5-1432710-G-T is described in ClinVar as Benign. ClinVar VariationId is 522347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 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.419-12C>A		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.419-12C>A		intron	N/A	ENSP00000270349.9	Q01959
	SLC6A3	ENST00000941790.1		c.419-12C>A		intron	N/A	ENSP00000611849.1
	SLC6A3	ENST00000713696.1		c.419-12C>A		intron	N/A	ENSP00000519000.1	A0AAQ5BGN6

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47180 AN: 151876 Hom.: 8274 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.305 AC: 75405 AN: 246960 AF XY: 0.304

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.516

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.245 AC: 356468 AN: 1453632 Hom.: 49269 Cov.: 31 AF XY: 0.250 AC XY: 180725 AN XY: 723554

African (AFR) AF: 0.449 AC: 14956 AN: 33312

American (AMR) AF: 0.352 AC: 15620 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7226 AN: 26090

East Asian (EAS) AF: 0.529 AC: 20956 AN: 39588

South Asian (SAS) AF: 0.420 AC: 36162 AN: 86056

European-Finnish (FIN) AF: 0.285 AC: 15187 AN: 53232

Middle Eastern (MID) AF: 0.264 AC: 1518 AN: 5746

European-Non Finnish (NFE) AF: 0.207 AC: 228694 AN: 1105062

Other (OTH) AF: 0.268 AC: 16149 AN: 60168

GnomAD4 genome AF: 0.311 AC: 47229 AN: 151994 Hom.: 8283 Cov.: 32 AF XY: 0.318 AC XY: 23605 AN XY: 74266

African (AFR) AF: 0.440 AC: 18240 AN: 41448

American (AMR) AF: 0.334 AC: 5102 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 975 AN: 3466

East Asian (EAS) AF: 0.525 AC: 2694 AN: 5132

South Asian (SAS) AF: 0.415 AC: 1997 AN: 4808

European-Finnish (FIN) AF: 0.294 AC: 3104 AN: 10574

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14254 AN: 67964

Other (OTH) AF: 0.283 AC: 598 AN: 2110

Alfa AF: 0.240 Hom.: 20943

Bravo AF: 0.317

Asia WGS AF: 0.445 AC: 1546 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Classic dopamine transporter deficiency syndrome (2)
-	-	2	not provided (2)
-	-	1	Parkinsonism-dystonia, infantile (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.1
DANN	Benign	0.36
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.040		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: rs460000; hg19: chr5-1432825; COSMIC: COSV54363070;