Genetic Variant HTR3A:p.Leu459Leu (chr11-113989703-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000869.6(HTR3A):c.1377A>G(p.Leu459Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,613,658 control chromosomes in the GnomAD database, including 43,846 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 0.26 ( 5271 hom., cov: 32)

Exomes 𝑓: 0.23 ( 38575 hom. )

Consequence

HTR3A
NM_000869.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50

Publications

57 publications found

Variant links:

Genes affected

HTR3A (HGNC:5297): (5-hydroxytryptamine receptor 3A) The product of this gene belongs to the ligand-gated ion channel receptor superfamily. This gene encodes subunit A of the type 3 receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor causes fast, depolarizing responses in neurons after activation. It appears that the heteromeric combination of A and B subunits is necessary to provide the full functional features of this receptor, since either subunit alone results in receptors with very low conductance and response amplitude. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

HTR3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP7

Synonymous conserved (PhyloP=1.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR3A	NM_000869.6 link	c.1377A>G	p.Leu459Leu	synonymous_variant	Exon 9 of 9	ENST00000504030.7	NP_000860.3	P46098-1B4E398
HTR3A	NM_213621.4 link	c.1473A>G	p.Leu491Leu	synonymous_variant	Exon 8 of 8		NP_998786.3	P46098-2B4E398
HTR3A	NM_001161772.3 link	c.1332A>G	p.Leu444Leu	synonymous_variant	Exon 9 of 9		NP_001155244.1	P46098-3
HTR3A	NR_046363.2 link	n.1434A>G		non_coding_transcript_exon_variant	Exon 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR3A	ENST00000504030.7 link	c.1377A>G	p.Leu459Leu	synonymous_variant	Exon 9 of 9	1	NM_000869.6	ENSP00000424189.2		P46098-1

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38746

AN:

151972

Hom.:

5254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.296

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.289

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.218

Gnomad OTH

AF:

0.254

GnomAD2 exomes

AF:

0.264

AC:

66232

AN:

250986

AF XY:

0.255

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.409

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.296

Gnomad FIN exome

AF:

0.251

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.238

GnomAD4 exome

AF:

0.226

AC:

330158

AN:

1461566

Hom.:

38575

Cov.:

AF XY:

0.225

AC XY:

163816

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.296

AC:

9914

AN:

33476

American (AMR)

AF:

0.390

AC:

17457

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6914

AN:

26136

East Asian (EAS)

AF:

0.266

AC:

10548

AN:

39700

South Asian (SAS)

AF:

0.245

AC:

21173

AN:

86258

European-Finnish (FIN)

AF:

0.250

AC:

13282

AN:

53158

Middle Eastern (MID)

AF:

0.213

AC:

1231

AN:

5768

European-Non Finnish (NFE)

AF:

0.212

AC:

235276

AN:

1111954

Other (OTH)

AF:

0.238

AC:

14363

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

16383

32766

49149

65532

81915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8290

16580

24870

33160

41450

<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:

0.255

AC:

38804

AN:

152092

Hom.:

5271

Cov.:

AF XY:

0.258

AC XY:

19186

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.296

AC:

12286

AN:

41472

American (AMR)

AF:

0.306

AC:

4675

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

931

AN:

3468

East Asian (EAS)

AF:

0.288

AC:

1489

AN:

5162

South Asian (SAS)

AF:

0.257

AC:

1238

AN:

4826

European-Finnish (FIN)

AF:

0.244

AC:

2577

AN:

10580

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.219

AC:

14858

AN:

67984

Other (OTH)

AF:

0.256

AC:

542

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1495

2990

4485

5980

7475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.232

Hom.:

9456

Bravo

AF:

0.262

Asia WGS

AF:

0.275

AC:

958

AN:

3478

EpiCase

AF:

0.217

EpiControl

AF:

0.226

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.6

(source)

DANN

Benign

0.64

PhyloP100

1.5

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