5-1416027-C-A

Variant names:

• chr5-1416027-C-A
• rs40358
• NM_001044.5:c.1031+71G>T

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.1031+71G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 1,168,044 control chromosomes in the GnomAD database, including 411,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49818 hom., cov: 34)
  • Exomes 𝑓: 0.84 (361685 hom.)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.14
• Publications: 16 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=-0.99).
• BP6: Variant 5-1416027-C-A is Benign according to our data. Variant chr5-1416027-C-A is described in ClinVar as Benign. ClinVar VariationId is 1185399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.1031+71G>T		intron_variant	Intron 7 of 14	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.1031+71G>T		intron_variant	Intron 7 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.896+71G>T		intron_variant	Intron 6 of 14			ENSP00000519000.1
SLC6A3	ENST00000511750.1	n.481+71G>T		intron_variant	Intron 1 of 1	4
SLC6A3	ENST00000713697.1	n.1031+71G>T		intron_variant	Intron 7 of 10			ENSP00000519001.1

Frequencies

GnomAD3 genomes AF: 0.806 AC: 122555 AN: 152074 Hom.: 49793 Cov.: 34

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.801

GnomAD4 exome AF: 0.842 AC: 855511 AN: 1015852 Hom.: 361685 AF XY: 0.845 AC XY: 442322 AN XY: 523706

African (AFR) AF: 0.711 AC: 17761 AN: 24974

American (AMR) AF: 0.778 AC: 33348 AN: 42852

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 19028 AN: 23228

East Asian (EAS) AF: 0.634 AC: 23698 AN: 37368

South Asian (SAS) AF: 0.873 AC: 67122 AN: 76922

European-Finnish (FIN) AF: 0.894 AC: 45959 AN: 51412

Middle Eastern (MID) AF: 0.753 AC: 3699 AN: 4912

European-Non Finnish (NFE) AF: 0.857 AC: 606888 AN: 708356

Other (OTH) AF: 0.829 AC: 38008 AN: 45828

GnomAD4 genome AF: 0.806 AC: 122629 AN: 152192 Hom.: 49818 Cov.: 34 AF XY: 0.809 AC XY: 60209 AN XY: 74408

African (AFR) AF: 0.717 AC: 29743 AN: 41508

American (AMR) AF: 0.813 AC: 12433 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2838 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3265 AN: 5170

South Asian (SAS) AF: 0.859 AC: 4140 AN: 4818

European-Finnish (FIN) AF: 0.882 AC: 9359 AN: 10606

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.855 AC: 58166 AN: 68002

Other (OTH) AF: 0.802 AC: 1691 AN: 2108

Alfa AF: 0.829 Hom.: 83879

Bravo AF: 0.790

Asia WGS AF: 0.764 AC: 2660 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Classic dopamine transporter deficiency syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.0080
DANN	Benign	0.48
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs40358; hg19: chr5-1416142; COSMIC: COSV54365179;