5-1406260-C-T

Variant names:

• chr5-1406260-C-T
• rs6880875
• NM_001044.5:c.1527G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000270349.12(SLC6A3):​c.1527G>A​(p.Gln509Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,612,970 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (158 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (162 hom.)
• Consequence: SLC6A3 ENST00000270349.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0850
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-1406260-C-T is Benign according to our data. Variant chr5-1406260-C-T is described in ClinVar as Benign. ClinVar VariationId is 470635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.085 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0862 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000270349.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	NM_001044.5	MANE Select	c.1527G>A	p.Gln509Gln	synonymous	Exon 12 of 15	NP_001035.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	ENST00000270349.12	TSL:1 MANE Select	c.1527G>A	p.Gln509Gln	synonymous	Exon 12 of 15	ENSP00000270349.9
	SLC6A3	ENST00000713696.1		c.1392G>A	p.Gln464Gln	synonymous	Exon 11 of 15	ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3924 AN: 152214 Hom.: 158 Cov.: 33

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00697 AC: 1745 AN: 250378 AF XY: 0.00513

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000408

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00277 AC: 4047 AN: 1460638 Hom.: 162 Cov.: 32 AF XY: 0.00238 AC XY: 1731 AN XY: 726636

African (AFR) AF: 0.0925 AC: 3096 AN: 33468

American (AMR) AF: 0.00577 AC: 258 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52260

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.000185 AC: 206 AN: 1111958

Other (OTH) AF: 0.00585 AC: 353 AN: 60378

GnomAD4 genome AF: 0.0258 AC: 3931 AN: 152332 Hom.: 158 Cov.: 33 AF XY: 0.0249 AC XY: 1852 AN XY: 74486

African (AFR) AF: 0.0886 AC: 3681 AN: 41562

American (AMR) AF: 0.0115 AC: 176 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00964 Hom.: 113

Bravo AF: 0.0301

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Parkinsonism-dystonia, infantile (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.7
DANN	Benign	0.57
PhyloP100		-0.085
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: rs6880875; hg19: chr5-1406375;