dbSNP rs28914830: SLC6A4:c.1205-33C>T (chr17-30211457-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001045.6(SLC6A4):c.1205-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,318,042 control chromosomes in the GnomAD database, including 258 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 0.024 ( 123 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 135 hom. )

Consequence

SLC6A4
NM_001045.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.117

Publications

4 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 -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 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=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.077 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A4	NM_001045.6 link	c.1205-33C>T		intron_variant	Intron 9 of 14	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1 link	c.1205-33C>T		intron_variant	Intron 9 of 14		NM_001045.6	ENSP00000498537.1

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3621

AN:

152154

Hom.:

125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0794

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.00684

AC:

1698

AN:

248160

AF XY:

0.00513

show subpopulations

Gnomad AFR exome

AF:

0.0802

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.00483

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000943

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00608

GnomAD4 exome

AF:

0.00362

AC:

4215

AN:

1165770

Hom.:

135

Cov.:

AF XY:

0.00317

AC XY:

1880

AN XY:

593906

show subpopulations

African (AFR)

AF:

0.0860

AC:

2407

AN:

27976

American (AMR)

AF:

0.00636

AC:

280

AN:

44008

Ashkenazi Jewish (ASJ)

AF:

0.00443

AC:

107

AN:

24176

East Asian (EAS)

AF:

0.00

AC:

AN:

38324

South Asian (SAS)

AF:

0.000362

AC:

AN:

80088

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

53016

Middle Eastern (MID)

AF:

0.0144

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

0.00103

AC:

866

AN:

842358

Other (OTH)

AF:

0.00881

AC:

446

AN:

50614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

194

389

583

778

972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0238

AC:

3627

AN:

152272

Hom.:

123

Cov.:

AF XY:

0.0233

AC XY:

1734

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0793

AC:

3293

AN:

41530

American (AMR)

AF:

0.0114

AC:

174

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68030

Other (OTH)

AF:

0.0208

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.0268

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.1

(source)

DANN

Benign

0.60

PhyloP100

-0.12

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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