5-1423790-A-G

Variant names:

• chr5-1423790-A-G
• rs464049
• NM_001044.5:c.654-1776T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001044.5(SLC6A3):​c.654-1776T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,088 control chromosomes in the GnomAD database, including 21,979 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 0.53 (21979 hom., cov: 33)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.865
• Publications: 43 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=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.654-1776T>C		intron_variant	Intron 4 of 14	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.654-1776T>C		intron_variant	Intron 4 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.654-1776T>C		intron_variant	Intron 4 of 14			ENSP00000519000.1
SLC6A3	ENST00000713697.1	n.654-1776T>C		intron_variant	Intron 4 of 10			ENSP00000519001.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80294 AN: 151970 Hom.: 21941 Cov.: 33

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.495

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80395 AN: 152088 Hom.: 21979 Cov.: 33 AF XY: 0.537 AC XY: 39944 AN XY: 74342

African (AFR) AF: 0.636 AC: 26403 AN: 41492

American (AMR) AF: 0.547 AC: 8350 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1713 AN: 3468

East Asian (EAS) AF: 0.650 AC: 3357 AN: 5164

South Asian (SAS) AF: 0.654 AC: 3153 AN: 4820

European-Finnish (FIN) AF: 0.554 AC: 5855 AN: 10576

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29992 AN: 67976

Other (OTH) AF: 0.500 AC: 1056 AN: 2112

Alfa AF: 0.461 Hom.: 35973

Bravo AF: 0.526

Asia WGS AF: 0.660 AC: 2294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.28
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs464049; hg19: chr5-1423905;