rs757417973

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001044.5(SLC6A3):c.77C>T(p.Pro26Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P26P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

SLC6A3
NM_001044.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.105421245).

BP6

Variant 5-1443121-G-A is Benign according to our data. Variant chr5-1443121-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 582040.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000789 (12/152182) while in subpopulation AMR AF = 0.000327 (5/15278). AF 95% confidence interval is 0.000129. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	NM_001044.5	MANE Select	c.77C>T	p.Pro26Leu	missense	Exon 2 of 15	NP_001035.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC6A3	ENST00000270349.12	TSL:1 MANE Select	c.77C>T	p.Pro26Leu	missense	Exon 2 of 15	ENSP00000270349.9
SLC6A3	ENST00000713696.1		c.77C>T	p.Pro26Leu	missense	Exon 2 of 15	ENSP00000519000.1
SLC6A3	ENST00000713698.1		c.77C>T	p.Pro26Leu	missense	Exon 2 of 5	ENSP00000519002.1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000159

AC:

AN:

251348

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33478

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1112006

Other (OTH)

AF:

0.0000662

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.000327

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00143

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Parkinsonism-dystonia, infantile (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.2

PhyloP100

3.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

REVEL

Benign

0.24

Sift

Benign

0.098

Sift4G

Uncertain

0.045

Polyphen

0.90

Vest4

0.28

MutPred

0.30

Loss of sheet (P = 0.0084)

MVP

0.54

MPC

0.61

ClinPred

0.055

GERP RS

3.5

Varity_R

0.053

gMVP

0.46

Mutation Taster

=75/25

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over