5-1414692-G-A

Position:

chr5-1414692-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001044.5(SLC6A3):c.1155C>T(p.Asp385=) 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:3B:2

Conservation

PhyloP100: -0.921

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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: {Likely_benign=2, Uncertain_significance=3}. 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A3	NM_001044.5 linkuse as main transcript	c.1155C>T	p.Asp385=	splice_region_variant, synonymous_variant	8/15	ENST00000270349.12	NP_001035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A3	ENST00000270349.12 linkuse as main transcript	c.1155C>T	p.Asp385=	splice_region_variant, synonymous_variant	8/15	1	NM_001044.5	ENSP00000270349	P1
SLC6A3	ENST00000511750.1 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000493

AC:

123

AN:

249568

Hom.:

AF XY:

0.000414

AC XY:

AN XY:

135402

show subpopulations

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 SAS exome

AF:

0.000588

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.:

Cov.:

AF XY:

0.000434

AC XY:

315

AN XY:

726408

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.000582

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0000575

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.000862

GnomAD4 genome

AF:

0.000440

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000652

Hom.:

Bravo

AF:

0.000502

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	SLC6A3: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

Parkinsonism-dystonia, infantile

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over