rs6355

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1BS2_Supporting

The NM_001045.6(SLC6A4):c.167G>C(p.Gly56Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,614,164 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 23 hom., cov: 32)

Exomes 𝑓: 0.018 ( 287 hom. )

Consequence

SLC6A4
NM_001045.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.477

Publications

108 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038065612).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0115 (1745/152280) while in subpopulation NFE AF = 0.0198 (1346/68022). AF 95% confidence interval is 0.0189. There are 23 homozygotes in GnomAd4. There are 753 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1745 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.167G>C	p.Gly56Ala	missense_variant	Exon 3 of 15	ENST00000650711.1	NP_001036.1	P31645-1B2R7Y7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A4	ENST00000650711.1 link	c.167G>C	p.Gly56Ala	missense_variant	Exon 3 of 15		NM_001045.6	ENSP00000498537.1	P31645-1
SLC6A4	ENST00000261707.7 link	c.167G>C	p.Gly56Ala	missense_variant	Exon 3 of 15	1		ENSP00000261707.3	P31645-1
SLC6A4	ENST00000394821.2 link	c.167G>C	p.Gly56Ala	missense_variant	Exon 3 of 15	1		ENSP00000378298.2	J3KPR9
SLC6A4	ENST00000401766.6 link	c.167G>C	p.Gly56Ala	missense_variant	Exon 2 of 14	5		ENSP00000385822.2	P31645-1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1744

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00954

Gnomad FIN

AF:

0.00660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0120

AC:

3024

AN:

251486

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00463

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.0180

AC:

26274

AN:

1461884

Hom.:

287

Cov.:

AF XY:

0.0177

AC XY:

12880

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

33480

American (AMR)

AF:

0.00487

AC:

218

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0102

AC:

878

AN:

86258

European-Finnish (FIN)

AF:

0.00784

AC:

419

AN:

53420

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0213

AC:

23719

AN:

1112006

Other (OTH)

AF:

0.0140

AC:

846

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1512

3024

4535

6047

7559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

944

1888

2832

3776

4720

<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:

0.0115

AC:

1745

AN:

152280

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

753

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00383

AC:

159

AN:

41554

American (AMR)

AF:

0.00542

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00976

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00660

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0198

AC:

1346

AN:

68022

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

178

268

357

446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0167

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0215

AC:

185

ExAC

AF:

0.0123

AC:

1499

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0187

EpiControl

AF:

0.0167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

7.5

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.70

.;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;.

PhyloP100

0.48

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.10

Sift

Uncertain

0.018

D;D;.

Sift4G

Benign

0.23

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.040

MPC

0.48

ClinPred

0.0028

GERP RS

0.70

Varity_R

0.049

gMVP

0.30

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over