Variant chr20-62216362-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007232.3(HRH3):c.982G>T(p.Ala328Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,577,572 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

HRH3
NM_007232.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Variant links:

Genes affected

HRH3 (HGNC:5184): (histamine receptor H3) Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3 and H4. This gene encodes one of the histamine receptors (H3) which belongs to the family 1 of G protein-coupled receptors. It is an integral membrane protein and can regulate neurotransmitter release. This receptor can also increase voltage-dependent calcium current in smooth muscles and innervates the blood vessels and the heart in cardiovascular system. [provided by RefSeq, Jul 2008]

HRH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05789876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRH3	NM_007232.3 linkuse as main transcript	c.982G>T	p.Ala328Ser	missense_variant	3/3	ENST00000340177.10	NP_009163.2	Q9Y5N1-1
HRH3	XM_005260266.4 linkuse as main transcript	c.982G>T	p.Ala328Ser	missense_variant	3/4		XP_005260323.1	Q9Y5N1-2
HRH3	XM_017027623.2 linkuse as main transcript	c.940G>T	p.Ala314Ser	missense_variant	3/4		XP_016883112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRH3	ENST00000340177.10 linkuse as main transcript	c.982G>T	p.Ala328Ser	missense_variant	3/3	1	NM_007232.3	ENSP00000342560.5		Q9Y5N1-1
HRH3	ENST00000317393.10 linkuse as main transcript	c.822-80G>T		intron_variant		1		ENSP00000321482.7		A0A0A0MR48

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000207

AC:

AN:

193522

Hom.:

AF XY:

0.0000286

AC XY:

AN XY:

104938

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000594

GnomAD4 exome

AF:

0.0000168

AC:

AN:

1425350

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

705264

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000326

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.15e-7

Gnomad4 OTH exome

AF:

0.000170

GnomAD4 genome

AF:

0.000145

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000385

ExAC

AF:

0.00000839

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

The c.982G>T (p.A328S) alteration is located in exon 3 (coding exon 3) of the HRH3 gene. This alteration results from a G to T substitution at nucleotide position 982, causing the alanine (A) at amino acid position 328 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.070

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.67

M_CAP

Benign

0.014

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.51

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.69

REVEL

Benign

0.091

Sift

Benign

0.27

Sift4G

Benign

0.81

Polyphen

0.0060

Vest4

0.15

MutPred

0.41

Gain of phosphorylation at A328 (P = 0.0017);

MVP

0.81

MPC

0.38

ClinPred

0.021

GERP RS

3.6

Varity_R

0.069

gMVP

0.79

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over