rs2975223

Variant names:

• chr5-1443488-T-C
• rs2975223
• NM_001044.5:c.-45-246A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001044.5(SLC6A3):​c.-45-246A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 151,378 control chromosomes in the GnomAD database, including 20,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (20008 hom., cov: 32)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.87
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-1443488-T-C is Benign according to our data. Variant chr5-1443488-T-C is described in ClinVar as Benign. ClinVar VariationId is 1261279.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.-45-246A>G		intron_variant	Intron 1 of 14	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.-45-246A>G		intron_variant	Intron 1 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.-45-246A>G		intron_variant	Intron 1 of 14			ENSP00000519000.1
SLC6A3	ENST00000713698.1	c.-45-246A>G		intron_variant	Intron 1 of 4			ENSP00000519002.1
SLC6A3	ENST00000713697.1	n.-45-246A>G		intron_variant	Intron 1 of 10			ENSP00000519001.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75864 AN: 151260 Hom.: 19981 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.519

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

GnomAD4 genome AF: 0.502 AC: 75946 AN: 151378 Hom.: 20008 Cov.: 32 AF XY: 0.500 AC XY: 36939 AN XY: 73920

African (AFR) AF: 0.372 AC: 15371 AN: 41294

American (AMR) AF: 0.480 AC: 7324 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2125 AN: 3460

East Asian (EAS) AF: 0.169 AC: 870 AN: 5136

South Asian (SAS) AF: 0.512 AC: 2458 AN: 4800

European-Finnish (FIN) AF: 0.554 AC: 5793 AN: 10458

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.594 AC: 40176 AN: 67692

Other (OTH) AF: 0.522 AC: 1098 AN: 2104

Alfa AF: 0.538 Hom.: 2740

Bravo AF: 0.487

Asia WGS AF: 0.372 AC: 1293 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 31, 2019

GeneDx

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	-0.85
CADD	Benign	0.045
DANN	Benign	0.49
PhyloP100		-2.9
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: rs2975223; hg19: chr5-1443603; COSMIC: COSV54362263;