Genetic Variant SLC6A4:c.-220-25G>A (chr17-30222940-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.-220-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 854,130 control chromosomes in the GnomAD database, including 132 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.010 ( 15 hom., cov: 33)

Exomes 𝑓: 0.015 ( 117 hom. )

Consequence

SLC6A4
NM_001045.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.824

Publications

7 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00996 (1516/152248) while in subpopulation SAS AF = 0.0184 (89/4828). AF 95% confidence interval is 0.0153. There are 15 homozygotes in GnomAd4. There are 705 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1516 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.-220-25G>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.-220-25G>A	intron_variant	Intron 1 of 14		NM_001045.6	ENSP00000498537.1
SLC6A4	ENST00000261707.7 link	c.-220-25G>A	intron_variant	Intron 1 of 14	1		ENSP00000261707.3
SLC6A4	ENST00000394821.2 link	c.-220-25G>A	intron_variant	Intron 1 of 14	1		ENSP00000378298.2
SLC6A4	ENST00000401766.6 link	c.-123-859G>A	intron_variant	Intron 1 of 13	5		ENSP00000385822.2

Frequencies

GnomAD3 genomes

AF:

0.00995

AC:

1513

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.0124

GnomAD4 exome

AF:

0.0153

AC:

10763

AN:

701882

Hom.:

117

Cov.:

AF XY:

0.0155

AC XY:

5596

AN XY:

360610

show subpopulations

African (AFR)

AF:

0.00290

AC:

AN:

15196

American (AMR)

AF:

0.00389

AC:

108

AN:

27758

Ashkenazi Jewish (ASJ)

AF:

0.0211

AC:

276

AN:

13100

East Asian (EAS)

AF:

0.000181

AC:

AN:

11026

South Asian (SAS)

AF:

0.0213

AC:

1438

AN:

67364

European-Finnish (FIN)

AF:

0.00889

AC:

193

AN:

21710

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

3492

European-Non Finnish (NFE)

AF:

0.0160

AC:

8233

AN:

515390

Other (OTH)

AF:

0.0159

AC:

426

AN:

26846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

535

1071

1606

2142

2677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.00996

AC:

1516

AN:

152248

Hom.:

Cov.:

AF XY:

0.00947

AC XY:

705

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41534

American (AMR)

AF:

0.00425

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0184

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00669

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1047

AN:

68014

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00597

Hom.:

Bravo

AF:

0.00926

Asia WGS

AF:

0.0100

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

4.9

(source)

DANN

Benign

0.48

PhyloP100

0.82

BranchPoint Hunter

3.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over