5-1400883-CGA-C

Variant names:

• chr5-1400883-CGA-C
• rs28364999
• NM_001044.5:c.1839+30_1839+31delTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001044.5(SLC6A3):​c.1839+30_1839+31delTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,518,040 control chromosomes in the GnomAD database, including 287 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 33)
  • Exomes 𝑓: 0.017 (263 hom.)
• Consequence: SLC6A3 NM_001044.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.786
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 5-1400883-CGA-C is Benign according to our data. Variant chr5-1400883-CGA-C is described in ClinVar as [Likely_benign]. Clinvar id is 1207981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0124 (1895/152278) while in subpopulation SAS AF = 0.0223 (107/4806). AF 95% confidence interval is 0.0188. There are 24 homozygotes in GnomAd4. There are 903 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.1839+30_1839+31delTC		intron_variant	Intron 14 of 14	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.1839+30_1839+31delTC		intron_variant	Intron 14 of 14	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000512002.2	n.220+30_220+31delTC		intron_variant	Intron 2 of 2	1
SLC6A3	ENST00000713696.1	c.*34+30_*34+31delTC		intron_variant	Intron 14 of 14			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1895 AN: 152158 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0147 AC: 2541 AN: 172698 AF XY: 0.0159

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00572

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.000157

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0170 AC: 23189 AN: 1365762 Hom.: 263 AF XY: 0.0176 AC XY: 11942 AN XY: 677544

African (AFR) AF: 0.00311 AC: 97 AN: 31212

American (AMR) AF: 0.00656 AC: 247 AN: 37636

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 341 AN: 25072

East Asian (EAS) AF: 0.000110 AC: 4 AN: 36308

South Asian (SAS) AF: 0.0233 AC: 1857 AN: 79582

European-Finnish (FIN) AF: 0.0176 AC: 877 AN: 49834

Middle Eastern (MID) AF: 0.0117 AC: 66 AN: 5626

European-Non Finnish (NFE) AF: 0.0180 AC: 18824 AN: 1043656

Other (OTH) AF: 0.0154 AC: 876 AN: 56836

GnomAD4 genome AF: 0.0124 AC: 1895 AN: 152278 Hom.: 24 Cov.: 33 AF XY: 0.0121 AC XY: 903 AN XY: 74444

African (AFR) AF: 0.00289 AC: 120 AN: 41556

American (AMR) AF: 0.00974 AC: 149 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0223 AC: 107 AN: 4806

European-Finnish (FIN) AF: 0.0177 AC: 188 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1255 AN: 68016

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0171 Hom.: 6

Bravo AF: 0.0115

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism

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: rs28364999; hg19: chr5-1400998;