Genetic Variant NM_001045.6:c.344-1261C>T (chr17-30220192-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.344-1261C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 152,070 control chromosomes in the GnomAD database, including 39,279 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 0.69 ( 39279 hom., cov: 32)

Consequence

SLC6A4
NM_001045.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.301

Publications

16 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A4	NM_001045.6 link	c.344-1261C>T		intron_variant	Intron 3 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.344-1261C>T	intron_variant	Intron 3 of 14		NM_001045.6	ENSP00000498537.1	P31645-1
SLC6A4	ENST00000261707.7 link	c.344-1261C>T	intron_variant	Intron 3 of 14	1		ENSP00000261707.3	P31645-1
SLC6A4	ENST00000394821.2 link	c.344-1261C>T	intron_variant	Intron 3 of 14	1		ENSP00000378298.2	J3KPR9
SLC6A4	ENST00000401766.6 link	c.344-1261C>T	intron_variant	Intron 2 of 13	5		ENSP00000385822.2	P31645-1

Frequencies

GnomAD3 genomes

AF:

0.690

AC:

104814

AN:

151952

Hom.:

39263

Cov.:

show subpopulations

Gnomad AFR

AF:

0.362

Gnomad AMI

AF:

0.901

Gnomad AMR

AF:

0.791

Gnomad ASJ

AF:

0.827

Gnomad EAS

AF:

0.893

Gnomad SAS

AF:

0.822

Gnomad FIN

AF:

0.818

Gnomad MID

AF:

0.755

Gnomad NFE

AF:

0.810

Gnomad OTH

AF:

0.715

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.690

AC:

104854

AN:

152070

Hom.:

39279

Cov.:

AF XY:

0.695

AC XY:

51681

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.362

AC:

14980

AN:

41430

American (AMR)

AF:

0.791

AC:

12106

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.827

AC:

2872

AN:

3472

East Asian (EAS)

AF:

0.894

AC:

4631

AN:

5182

South Asian (SAS)

AF:

0.822

AC:

3954

AN:

4812

European-Finnish (FIN)

AF:

0.818

AC:

8659

AN:

10582

Middle Eastern (MID)

AF:

0.767

AC:

224

AN:

292

European-Non Finnish (NFE)

AF:

0.810

AC:

55092

AN:

67980

Other (OTH)

AF:

0.717

AC:

1516

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1359

2718

4076

5435

6794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.753

Hom.:

21139

Bravo

AF:

0.674

Asia WGS

AF:

0.807

AC:

2804

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.7

(source)

DANN

Benign

0.48

PhyloP100

0.30

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over