5-1394407-CGGGAGCA-C

Variant names:

• chr5-1394407-CGGGAGCA-C
• rs371613676
• ENST00000512002.2:n.565_571delTGCTCCC

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.*321_*327delTGCTCCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 495,176 control chromosomes in the GnomAD database, including 62 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 32)
  • Exomes 𝑓: 0.012 (44 hom.)
• Consequence: SLC6A3 NM_001044.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.669
• 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 5-1394407-CGGGAGCA-C is Benign according to our data. Variant chr5-1394407-CGGGAGCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 1181229.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1532/152146) while in subpopulation NFE AF = 0.0152 (1033/67980). AF 95% confidence interval is 0.0144. There are 18 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.*321_*327delTGCTCCC		3_prime_UTR_variant	Exon 15 of 15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000512002.2	n.565_571delTGCTCCC		non_coding_transcript_exon_variant	Exon 3 of 3	1
SLC6A3	ENST00000270349.12	c.*321_*327delTGCTCCC		3_prime_UTR_variant	Exon 15 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000713696.1	c.*379_*385delTGCTCCC		3_prime_UTR_variant	Exon 15 of 15			ENSP00000519000.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1532 AN: 152028 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.0123 AC: 4215 AN: 343030 Hom.: 44 AF XY: 0.0124 AC XY: 2224 AN XY: 179974

African (AFR) AF: 0.00408 AC: 41 AN: 10054

American (AMR) AF: 0.00459 AC: 68 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 80 AN: 10560

East Asian (EAS) AF: 0.000305 AC: 7 AN: 22926

South Asian (SAS) AF: 0.0119 AC: 470 AN: 39508

European-Finnish (FIN) AF: 0.0168 AC: 328 AN: 19496

Middle Eastern (MID) AF: 0.00724 AC: 11 AN: 1520

European-Non Finnish (NFE) AF: 0.0147 AC: 3000 AN: 204454

Other (OTH) AF: 0.0107 AC: 210 AN: 19690

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152146 Hom.: 18 Cov.: 32 AF XY: 0.00979 AC XY: 728 AN XY: 74368

African (AFR) AF: 0.00308 AC: 128 AN: 41500

American (AMR) AF: 0.00477 AC: 73 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4824

European-Finnish (FIN) AF: 0.0167 AC: 177 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0152 AC: 1033 AN: 67980

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.00851

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 01, 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		0.67
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371613676; hg19: chr5-1394522;