5-1394699-C-T

Variant names:

• chr5-1394699-C-T
• rs28363166
• ENST00000512002.2:n.280G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001044.5(SLC6A3):​c.*36G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,608,550 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (234 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (229 hom.)
• Consequence: SLC6A3 NM_001044.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.138
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-1394699-C-T is Benign according to our data. Variant chr5-1394699-C-T is described in ClinVar as [Benign]. Clinvar id is 1244976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.*36G>A		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.280G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
SLC6A3	ENST00000270349.12	c.*36G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.*94G>A		3_prime_UTR_variant	Exon 15 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4586 AN: 152174 Hom.: 232 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00812 AC: 2041 AN: 251448 AF XY: 0.00591

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00314 AC: 4567 AN: 1456258 Hom.: 229 Cov.: 28 AF XY: 0.00263 AC XY: 1910 AN XY: 724916

African (AFR) AF: 0.109 AC: 3633 AN: 33268

American (AMR) AF: 0.00597 AC: 267 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5762

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1107006

Other (OTH) AF: 0.00639 AC: 385 AN: 60228

GnomAD4 genome AF: 0.0302 AC: 4605 AN: 152292 Hom.: 234 Cov.: 33 AF XY: 0.0285 AC XY: 2122 AN XY: 74470

African (AFR) AF: 0.105 AC: 4361 AN: 41534

American (AMR) AF: 0.0106 AC: 162 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.00980 Hom.: 52

Bravo AF: 0.0347

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.89
CADD	Benign	0.11
DANN	Benign	0.52
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs28363166; hg19: chr5-1394814;