dbSNP rs28914827: SLC6A4:c.-124+28G>A (chr17-30222791-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1BS2_Supporting

The NM_001045.6(SLC6A4):c.-124+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,304,300 control chromosomes in the GnomAD database, including 266 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 0.011 ( 22 hom., cov: 32)

Exomes 𝑓: 0.019 ( 244 hom. )

Consequence

SLC6A4
NM_001045.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.453

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1739/152344) while in subpopulation NFE AF= 0.0197 (1340/68026). AF 95% confidence interval is 0.0188. There are 22 homozygotes in gnomad4. There are 749 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1739 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.-124+28G>A		intron_variant	Intron 2 of 14	ENST00000650711.1	NP_001036.1	P31645-1B2R7Y7

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A4	ENST00000650711.1 link	c.-124+28G>A	intron_variant	Intron 2 of 14		NM_001045.6	ENSP00000498537.1	P31645-1
SLC6A4	ENST00000261707.7 link	c.-124+28G>A	intron_variant	Intron 2 of 14	1		ENSP00000261707.3	P31645-1
SLC6A4	ENST00000394821.2 link	c.-124+28G>A	intron_variant	Intron 2 of 14	1		ENSP00000378298.2	J3KPR9
SLC6A4	ENST00000401766.6 link	c.-123-710G>A	intron_variant	Intron 1 of 13	5		ENSP00000385822.2	P31645-1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1738

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00536

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00951

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0119

GnomAD3 exomes

AF:

0.0116

AC:

1782

AN:

153340

Hom.:

AF XY:

0.0120

AC XY:

981

AN XY:

82046

show subpopulations

Gnomad AFR exome

AF:

0.00312

Gnomad AMR exome

AF:

0.00504

Gnomad ASJ exome

AF:

0.00344

Gnomad EAS exome

AF:

0.000538

Gnomad SAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.00629

Gnomad NFE exome

AF:

0.0208

Gnomad OTH exome

AF:

0.00894

GnomAD4 exome

AF:

0.0190

AC:

21917

AN:

1151956

Hom.:

244

Cov.:

AF XY:

0.0188

AC XY:

10617

AN XY:

564880

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.00513

Gnomad4 ASJ exome

AF:

0.00257

Gnomad4 EAS exome

AF:

0.000385

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.00702

Gnomad4 NFE exome

AF:

0.0218

Gnomad4 OTH exome

AF:

0.0148

GnomAD4 genome

AF:

0.0114

AC:

1739

AN:

152344

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

749

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00385

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00972

Gnomad4 FIN

AF:

0.00659

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0128

Hom.:

Bravo

AF:

0.0109

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.5

DANN

Benign

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over