rs2042449

Variant names:

• chr5-1416531-G-A
• rs2042449
• NM_001044.5:c.928-330C>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.928-330C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 453,554 control chromosomes in the GnomAD database, including 11,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3208 hom., cov: 32)
  • Exomes 𝑓: 0.22 (7900 hom.)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0360
• Publications: 21 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=-0.93).
• BP6: Variant 5-1416531-G-A is Benign according to our data. Variant chr5-1416531-G-A is described in ClinVar as Benign. ClinVar VariationId is 1247436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.928-330C>T		intron_variant	Intron 6 of 14	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.928-330C>T		intron_variant	Intron 6 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000511750.1	n.48C>T		non_coding_transcript_exon_variant	Exon 1 of 2	4
SLC6A3	ENST00000713696.1	c.793-330C>T		intron_variant	Intron 5 of 14			ENSP00000519000.1
SLC6A3	ENST00000713697.1	n.928-330C>T		intron_variant	Intron 6 of 10			ENSP00000519001.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30572 AN: 151182 Hom.: 3202 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.223 AC: 67423 AN: 302248 Hom.: 7900 Cov.: 0 AF XY: 0.227 AC XY: 36430 AN XY: 160686

African (AFR) AF: 0.140 AC: 1245 AN: 8876

American (AMR) AF: 0.213 AC: 2965 AN: 13942

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 1872 AN: 8888

East Asian (EAS) AF: 0.115 AC: 1977 AN: 17126

South Asian (SAS) AF: 0.272 AC: 11539 AN: 42450

European-Finnish (FIN) AF: 0.259 AC: 4127 AN: 15934

Middle Eastern (MID) AF: 0.219 AC: 275 AN: 1258

European-Non Finnish (NFE) AF: 0.224 AC: 39614 AN: 176876

Other (OTH) AF: 0.225 AC: 3809 AN: 16898

GnomAD4 genome AF: 0.202 AC: 30605 AN: 151306 Hom.: 3208 Cov.: 32 AF XY: 0.205 AC XY: 15182 AN XY: 73920

African (AFR) AF: 0.142 AC: 5838 AN: 41220

American (AMR) AF: 0.205 AC: 3123 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 729 AN: 3458

East Asian (EAS) AF: 0.132 AC: 666 AN: 5064

South Asian (SAS) AF: 0.281 AC: 1341 AN: 4764

European-Finnish (FIN) AF: 0.264 AC: 2773 AN: 10510

Middle Eastern (MID) AF: 0.222 AC: 64 AN: 288

European-Non Finnish (NFE) AF: 0.228 AC: 15448 AN: 67754

Other (OTH) AF: 0.209 AC: 437 AN: 2090

Alfa AF: 0.212 Hom.: 11042

Bravo AF: 0.190

Asia WGS AF: 0.228 AC: 791 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 17, 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	-0.93
CADD	Benign	0.69
DANN	Benign	0.39
PhyloP100		0.036
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: rs2042449; hg19: chr5-1416646;