5-1443383-G-A

Variant names:

• chr5-1443383-G-A
• rs2455391
• NM_001044.5:c.-45-141C>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.-45-141C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 699,060 control chromosomes in the GnomAD database, including 20,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3593 hom., cov: 34)
  • Exomes 𝑓: 0.24 (16862 hom.)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.777
• Publications: 6 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 5-1443383-G-A is Benign according to our data. Variant chr5-1443383-G-A is described in ClinVar as Benign. ClinVar VariationId is 1265152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.-45-141C>T		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.-45-141C>T		intron_variant	Intron 1 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.-45-141C>T		intron_variant	Intron 1 of 14			ENSP00000519000.1
SLC6A3	ENST00000713698.1	c.-45-141C>T		intron_variant	Intron 1 of 4			ENSP00000519002.1
SLC6A3	ENST00000713697.1	n.-45-141C>T		intron_variant	Intron 1 of 10			ENSP00000519001.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30375 AN: 152138 Hom.: 3580 Cov.: 34

Gnomad AFR AF: 0.0731

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.239 AC: 130891 AN: 546804 Hom.: 16862 AF XY: 0.243 AC XY: 70255 AN XY: 288892

African (AFR) AF: 0.0705 AC: 1127 AN: 15984

American (AMR) AF: 0.237 AC: 7797 AN: 32922

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 2921 AN: 17662

East Asian (EAS) AF: 0.131 AC: 4181 AN: 31812

South Asian (SAS) AF: 0.294 AC: 16496 AN: 56100

European-Finnish (FIN) AF: 0.288 AC: 9238 AN: 32068

Middle Eastern (MID) AF: 0.223 AC: 527 AN: 2362

European-Non Finnish (NFE) AF: 0.249 AC: 81584 AN: 327910

Other (OTH) AF: 0.234 AC: 7020 AN: 29984

GnomAD4 genome AF: 0.200 AC: 30408 AN: 152256 Hom.: 3593 Cov.: 34 AF XY: 0.202 AC XY: 15047 AN XY: 74436

African (AFR) AF: 0.0729 AC: 3030 AN: 41580

American (AMR) AF: 0.220 AC: 3358 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 543 AN: 3470

East Asian (EAS) AF: 0.145 AC: 750 AN: 5176

South Asian (SAS) AF: 0.284 AC: 1367 AN: 4820

European-Finnish (FIN) AF: 0.291 AC: 3079 AN: 10588

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17527 AN: 68008

Other (OTH) AF: 0.215 AC: 455 AN: 2112

Alfa AF: 0.220 Hom.: 634

Bravo AF: 0.186

Asia WGS AF: 0.213 AC: 737 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Aug 15, 2018

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	-0.89
CADD	Benign	0.26
DANN	Benign	0.48
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2455391; hg19: chr5-1443498;