dbSNP rs139646314: HTR3A:p.Val137Met (chr11-113983154-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000869.6(HTR3A):c.409G>A(p.Val137Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V137L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

HTR3A
NM_000869.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 10.0

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR3A	NM_000869.6 link	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 9	ENST00000504030.7	NP_000860.3	P46098-1B4E398
HTR3A	NM_213621.4 link	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 8		NP_998786.3	P46098-2B4E398
HTR3A	NM_001161772.3 link	c.364G>A	p.Val122Met	missense_variant	Exon 5 of 9		NP_001155244.1	P46098-3
HTR3A	NR_046363.2 link	n.627G>A		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR3A	ENST00000504030.7 link	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 9	1	NM_000869.6	ENSP00000424189.2		P46098-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251490

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000649

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.6

M;.;.;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

N;N;N;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D

Vest4

0.88

MVP

0.77

MPC

0.44

ClinPred

0.26

GERP RS

5.4

Varity_R

0.39

gMVP

0.79

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