NM_001045.6:c.1273A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001045.6(SLC6A4):c.1273A>G(p.Ile425Val) variant causes a missense change. The variant allele was found at a frequency of 0.000819 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 0 hom. )

Consequence

SLC6A4
NM_001045.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 4.23

Publications

69 publications found

Variant links:

Genes affected

SLC6A4 (HGNC:11050): (solute carrier family 6 member 4) This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]

SLC6A4 Gene-Disease associations (from GenCC):

autism spectrum disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SLC6A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020125896).

BS2

High AC in GnomAd4 at 107 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A4	NM_001045.6 link	c.1273A>G	p.Ile425Val	missense_variant	Exon 10 of 15	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1 link	c.1273A>G	p.Ile425Val	missense_variant	Exon 10 of 15		NM_001045.6	ENSP00000498537.1

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000740

AC:

186

AN:

251312

AF XY:

0.000729

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.000757

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000831

AC:

1214

AN:

1461396

Hom.:

Cov.:

AF XY:

0.000824

AC XY:

599

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33466

American (AMR)

AF:

0.00101

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000336

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.000992

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000847

AC:

942

AN:

1111680

Other (OTH)

AF:

0.000944

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.000703

AC:

107

AN:

152242

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41548

American (AMR)

AF:

0.000589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000893

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000725

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Behavior disorder

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Obsessive-compulsive disorder, susceptibility to

Other:1

Nov 01, 2003

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.080

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.56

N;N;.

PhyloP100

4.2

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.66

N;N;.

REVEL

Benign

0.25

Sift

Benign

0.52

T;T;.

Sift4G

Benign

0.63

T;T;T

Polyphen

0.022

B;B;.

Vest4

0.28

MVP

0.53

MPC

0.43

ClinPred

0.010

GERP RS

5.2

Varity_R

0.29

gMVP

0.14

Mutation Taster

=15/85

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over