rs8179035

chr5-1409111-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001044.5(SLC6A3):c.1413C>G(p.Val471=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,611,034 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (10 hom.)
• Consequence: SLC6A3 NM_001044.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.241

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 5-1409111-G-C is Benign according to our data. Variant chr5-1409111-G-C is described in ClinVar as [Benign]. Clinvar id is 470633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.241 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00406 (619/152294) while in subpopulation AFR AF= 0.0129 (536/41546). AF 95% confidence interval is 0.012. There are 4 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A3	NM_001044.5	c.1413C>G	p.Val471=	synonymous_variant	11/15	ENST00000270349.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A3	ENST00000270349.12	c.1413C>G	p.Val471=	synonymous_variant	11/15	1	NM_001044.5	P1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152176 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00132 AC: 324 AN: 245068 Hom.: 2 AF XY: 0.00105 AC XY: 139 AN XY: 132962

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000382

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000778 AC: 1135 AN: 1458740 Hom.: 10 Cov.: 32 AF XY: 0.000758 AC XY: 550 AN XY: 725514

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000583

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00406 AC: 619 AN: 152294 Hom.: 4 Cov.: 33 AF XY: 0.00407 AC XY: 303 AN XY: 74476

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00163 Hom.: 1

Bravo AF: 0.00456

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinsonism-dystonia, infantile Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

SLC6A3: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	6.8
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs8179035; hg19: chr5-1409226;