chr5-1443036-G-A

Position:

• chr5-1443036-G-A

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.162C>T​(p.Pro54Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,186 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: SLC6A3 NM_001044.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.268

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=-0.81).
• BP6: Variant 5-1443036-G-A is Benign according to our data. Variant chr5-1443036-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1443036-G-A is described in Lovd as [Likely_benign]. Variant chr5-1443036-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00638 (971/152296) while in subpopulation NFE AF= 0.0109 (742/68012). AF 95% confidence interval is 0.0103. There are 6 homozygotes in gnomad4. There are 455 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	Protein	UniProt
SLC6A3	NM_001044.5	c.162C>T	p.Pro54Pro	synonymous_variant	2/15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.162C>T	p.Pro54Pro	synonymous_variant	2/15	1	NM_001044.5	ENSP00000270349.9

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152178 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00704 AC: 1769 AN: 251378 Hom.: 13 AF XY: 0.00761 AC XY: 1034 AN XY: 135900

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.00882

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.0107 AC: 15663 AN: 1461890 Hom.: 105 Cov.: 33 AF XY: 0.0107 AC XY: 7772 AN XY: 727244

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00262

Gnomad4 SAS exome AF: 0.00988

Gnomad4 FIN exome AF: 0.00477

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00950

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152296 Hom.: 6 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74478

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00707 Hom.: 3

Bravo AF: 0.00656

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SLC6A3: BP4, BP7, BS1, BS2 -

Classic dopamine transporter deficiency syndrome Benign:2

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

Parkinsonism-dystonia, infantile Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.59

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: rs6351; hg19: chr5-1443151;