5-1394545-G-A

Variant names:

• chr5-1394545-G-A
• rs403798
• ENST00000512002.2:n.434C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000512002.2(SLC6A3):​n.434C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 703,522 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0097 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (31 hom.)
• Consequence: SLC6A3 ENST00000512002.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0280
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00969 (1476/152344) while in subpopulation AFR AF = 0.0259 (1076/41572). AF 95% confidence interval is 0.0246. There are 25 homozygotes in GnomAd4. There are 763 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.*190C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000512002.2	n.434C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
SLC6A3	ENST00000270349.12	c.*190C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.*248C>T		3_prime_UTR_variant	Exon 15 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152226 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00530 AC: 2920 AN: 551178 Hom.: 31 Cov.: 5 AF XY: 0.00561 AC XY: 1662 AN XY: 296346

African (AFR) AF: 0.0260 AC: 415 AN: 15984

American (AMR) AF: 0.00421 AC: 142 AN: 33694

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 32 AN: 18768

East Asian (EAS) AF: 0.0188 AC: 632 AN: 33572

South Asian (SAS) AF: 0.0132 AC: 803 AN: 60664

European-Finnish (FIN) AF: 0.00123 AC: 46 AN: 37318

Middle Eastern (MID) AF: 0.00804 AC: 32 AN: 3980

European-Non Finnish (NFE) AF: 0.00203 AC: 643 AN: 316772

Other (OTH) AF: 0.00575 AC: 175 AN: 30426

GnomAD4 genome AF: 0.00969 AC: 1476 AN: 152344 Hom.: 25 Cov.: 33 AF XY: 0.0102 AC XY: 763 AN XY: 74496

African (AFR) AF: 0.0259 AC: 1076 AN: 41572

American (AMR) AF: 0.00614 AC: 94 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5182

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68038

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00428 Hom.: 5

Bravo AF: 0.0108

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 27, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.63
PhyloP100		-0.028
Mutation Taster		=100/0	polymorphism

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: rs403798; hg19: chr5-1394660;