Genetic Variant SLC6A3:p.Pro26Arg (chr5-1443121-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001044.5(SLC6A3):c.77C>G(p.Pro26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SLC6A3
NM_001044.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.52

Publications

4 publications found

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 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

SLC6A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23471114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A3	NM_001044.5 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 15	ENST00000270349.12	NP_001035.1	Q01959

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A3	ENST00000270349.12 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 15	1	NM_001044.5	ENSP00000270349.9	Q01959
SLC6A3	ENST00000713696.1 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 15			ENSP00000519000.1
SLC6A3	ENST00000713698.1 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 5			ENSP00000519002.1
SLC6A3	ENST00000713697.1 link	n.77C>G		non_coding_transcript_exon_variant	Exon 2 of 11			ENSP00000519001.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251348

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1112006

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000197

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.23

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.2

PhyloP100

3.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

REVEL

Benign

0.13

Sift

Benign

0.16

Sift4G

Uncertain

0.050

Polyphen

0.013

Vest4

0.45

MutPred

0.25

Loss of sheet (P = 0.0126);

MVP

0.53

MPC

0.63

ClinPred

0.090

GERP RS

3.5

Varity_R

0.044

gMVP

0.45

Mutation Taster

=72/28

polymorphism

(source)

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

Publications

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chr5-1443121-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over