rs6346

Variant names:

• chr5-1443048-C-A
• rs6346
• NM_001044.5:c.150G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1443048-C-A
• chr5-1443048-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001044.5(SLC6A3):​c.150G>T​(p.Pro50Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00779 in 1,614,162 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P50P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.040 (455 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (387 hom.)
• Consequence: SLC6A3 NM_001044.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.98
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 5-1443048-C-A is Benign according to our data. Variant chr5-1443048-C-A is described in ClinVar as Benign. ClinVar VariationId is 470634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	NM_001044.5	MANE Select	c.150G>T	p.Pro50Pro	synonymous	Exon 2 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.150G>T	p.Pro50Pro	synonymous	Exon 2 of 15	ENSP00000270349.9
	SLC6A3	ENST00000713696.1		c.150G>T	p.Pro50Pro	synonymous	Exon 2 of 15	ENSP00000519000.1
	SLC6A3	ENST00000713698.1		c.150G>T	p.Pro50Pro	synonymous	Exon 2 of 5	ENSP00000519002.1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6138 AN: 152158 Hom.: 452 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0110 AC: 2773 AN: 251404 AF XY: 0.00816

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.00836

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00438 AC: 6406 AN: 1461886 Hom.: 387 Cov.: 33 AF XY: 0.00380 AC XY: 2764 AN XY: 727242

African (AFR) AF: 0.153 AC: 5117 AN: 33480

American (AMR) AF: 0.00888 AC: 397 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.000221 AC: 246 AN: 1112008

Other (OTH) AF: 0.00931 AC: 562 AN: 60396

GnomAD4 genome AF: 0.0405 AC: 6164 AN: 152276 Hom.: 455 Cov.: 33 AF XY: 0.0391 AC XY: 2915 AN XY: 74458

African (AFR) AF: 0.141 AC: 5842 AN: 41526

American (AMR) AF: 0.0156 AC: 239 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68030

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0106 Hom.: 41

Bravo AF: 0.0469

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

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	-0.69
CADD	Benign	3.3
DANN	Benign	0.51
PhyloP100		-3.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -7

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

Other links and lift over

dbSNP: rs6346; hg19: chr5-1443163;