dbSNP rs28914826: SLC6A4:c.-221+133G>A (chr17-30235480-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

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

The NM_001045.6(SLC6A4):c.-221+133G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 152,324 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 61 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC6A4
NM_001045.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.153

Publications

1 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 (BayesDel_noAF=-0.73).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (2010/152324) while in subpopulation AFR AF = 0.0462 (1922/41576). AF 95% confidence interval is 0.0445. There are 61 homozygotes in GnomAd4. There are 964 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2010 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.-221+133G>A		intron_variant	Intron 1 of 14	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SLC6A4	ENST00000650711.1 link	c.-221+133G>A	intron_variant	Intron 1 of 14		NM_001045.6	ENSP00000498537.1
SLC6A4	ENST00000261707.7 link	c.-221+133G>A	intron_variant	Intron 1 of 14	1		ENSP00000261707.3
SLC6A4	ENST00000394821.2 link	c.-221+133G>A	intron_variant	Intron 1 of 14	1		ENSP00000378298.2
SLC6A4	ENST00000401766.6 link	c.-124+133G>A	intron_variant	Intron 1 of 13	5		ENSP00000385822.2

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2009

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0463

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00765

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0132

AC:

2010

AN:

152324

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

964

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0462

AC:

1922

AN:

41576

American (AMR)

AF:

0.00418

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68020

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

189

283

378

472

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:

0.0116

Hom.:

Bravo

AF:

0.0146

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.7

(source)

DANN

Benign

0.92

PhyloP100

0.15

PromoterAI

-0.0053

Neutral

(source)

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over