rs28364996

Positions:

• chr5-1432571-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001044.5(SLC6A3):​c.546C>T​(p.Asn182=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,252 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (42 hom.)
• Consequence: SLC6A3 NM_001044.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.25

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-1432571-G-A is Benign according to our data. Variant chr5-1432571-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1432571-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00378 (576/152372) while in subpopulation NFE AF= 0.00328 (223/68026). AF 95% confidence interval is 0.00293. There are 6 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A3	NM_001044.5	c.546C>T	p.Asn182=	synonymous_variant	4/15	ENST00000270349.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A3	ENST00000270349.12	c.546C>T	p.Asn182=	synonymous_variant	4/15	1	NM_001044.5	P1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 576 AN: 152254 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000747

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00449 AC: 1128 AN: 251456 Hom.: 10 AF XY: 0.00430 AC XY: 584 AN XY: 135910

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00362 AC: 5291 AN: 1461880 Hom.: 42 Cov.: 33 AF XY: 0.00353 AC XY: 2564 AN XY: 727244

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00139

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152372 Hom.: 6 Cov.: 33 AF XY: 0.00494 AC XY: 368 AN XY: 74510

Gnomad4 AFR AF: 0.000745

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic dopamine transporter deficiency syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC6A3: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2021	- -

Parkinsonism-dystonia, infantile Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.5
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs28364996; hg19: chr5-1432686;