5-1414692-G-A

Variant names:

• chr5-1414692-G-A
• rs145114326
• NM_001044.5:c.1155C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001044.5(SLC6A3):​c.1155C>T​(p.Asp385Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,612,378 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: SLC6A3 NM_001044.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002790
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.921

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-1414692-G-A is Benign according to our data. Variant chr5-1414692-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538065.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr5-1414692-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.921 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00044 (67/152182) while in subpopulation EAS AF = 0.00193 (10/5186). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5	c.1155C>T	p.Asp385Asp	splice_region_variant, synonymous_variant	Exon 8 of 15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12	c.1155C>T	p.Asp385Asp	splice_region_variant, synonymous_variant	Exon 8 of 15	1	NM_001044.5	ENSP00000270349.9
SLC6A3	ENST00000511750.1	n.*49C>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000493 AC: 123 AN: 249568 AF XY: 0.000414

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.000433 AC: 632 AN: 1460196 Hom.: 2 Cov.: 32 AF XY: 0.000434 AC XY: 315 AN XY: 726408

Gnomad4 AFR exome AF: 0.000747 AC: 25 AN: 33472

Gnomad4 AMR exome AF: 0.000582 AC: 26 AN: 44676

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26128

Gnomad4 EAS exome AF: 0.00151 AC: 60 AN: 39696

Gnomad4 SAS exome AF: 0.000348 AC: 30 AN: 86246

Gnomad4 FIN exome AF: 0.0000575 AC: 3 AN: 52136

Gnomad4 NFE exome AF: 0.000384 AC: 427 AN: 1111754

Gnomad4 Remaining exome AF: 0.000862 AC: 52 AN: 60348

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74406

Gnomad4 AFR AF: 0.000313 AC: 0.000313313 AN: 0.000313313

Gnomad4 AMR AF: 0.000458 AC: 0.000457696 AN: 0.000457696

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00193 AC: 0.00192827 AN: 0.00192827

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000500 AC: 0.000500191 AN: 0.000500191

Gnomad4 OTH AF: 0.00142 AC: 0.00141911 AN: 0.00141911

Alfa AF: 0.000674 Hom.: 2

Bravo AF: 0.000502

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC6A3: BP4, BP7 -

Tobacco addiction, susceptibility to;C5700336:Classic dopamine transporter deficiency syndrome Uncertain:1

Sep 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Parkinsonism-dystonia, infantile Uncertain:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 385 of the SLC6A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SLC6A3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs145114326, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SLC6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 538065). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Nov 30, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.60
DANN	Benign	0.88
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.060
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

Publications

LitVar

Other links and lift over

dbSNP: rs145114326; hg19: chr5-1414807; COSMIC: COSV99547695; COSMIC: COSV99547695;