20-62216366-C-T

Variant names:

• chr20-62216366-C-T
• rs3787430
• NM_007232.3:c.978G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_007232.3(HRH3):​c.978G>A​(p.Pro326Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,571,248 control chromosomes in the GnomAD database, including 17,014 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 0.15 (1897 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15117 hom.)
• Consequence: HRH3 NM_007232.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.51
• Publications: 17 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026603937).
• BP7: Synonymous conserved (PhyloP=-4.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRH3	NM_007232.3	c.978G>A	p.Pro326Pro	synonymous_variant	Exon 3 of 3	ENST00000340177.10	NP_009163.2
HRH3	XM_005260266.4	c.978G>A	p.Pro326Pro	synonymous_variant	Exon 3 of 4		XP_005260323.1
HRH3	XM_017027623.2	c.936G>A	p.Pro312Pro	synonymous_variant	Exon 3 of 4		XP_016883112.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRH3	ENST00000340177.10	c.978G>A	p.Pro326Pro	synonymous_variant	Exon 3 of 3	1	NM_007232.3	ENSP00000342560.5
HRH3	ENST00000317393.10	c.822-84G>A		intron_variant	Intron 3 of 4	1		ENSP00000321482.7

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23422 AN: 152110 Hom.: 1890 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0971

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.158 AC: 29378 AN: 185610 AF XY: 0.160

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.144 AC: 205004 AN: 1419020 Hom.: 15117 Cov.: 35 AF XY: 0.146 AC XY: 102467 AN XY: 701328

African (AFR) AF: 0.180 AC: 5864 AN: 32498

American (AMR) AF: 0.148 AC: 5755 AN: 39014

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 2519 AN: 25424

East Asian (EAS) AF: 0.144 AC: 5340 AN: 37160

South Asian (SAS) AF: 0.197 AC: 16146 AN: 82006

European-Finnish (FIN) AF: 0.134 AC: 6613 AN: 49342

Middle Eastern (MID) AF: 0.108 AC: 569 AN: 5262

European-Non Finnish (NFE) AF: 0.141 AC: 153962 AN: 1089660

Other (OTH) AF: 0.140 AC: 8236 AN: 58654

GnomAD4 genome AF: 0.154 AC: 23459 AN: 152228 Hom.: 1897 Cov.: 33 AF XY: 0.156 AC XY: 11574 AN XY: 74430

African (AFR) AF: 0.180 AC: 7491 AN: 41542

American (AMR) AF: 0.143 AC: 2193 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0971 AC: 337 AN: 3472

East Asian (EAS) AF: 0.162 AC: 839 AN: 5164

South Asian (SAS) AF: 0.202 AC: 975 AN: 4820

European-Finnish (FIN) AF: 0.142 AC: 1508 AN: 10610

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9679 AN: 67996

Other (OTH) AF: 0.137 AC: 289 AN: 2110

Alfa AF: 0.137 Hom.: 1398

Bravo AF: 0.155

TwinsUK AF: 0.142 AC: 527

ALSPAC AF: 0.144 AC: 556

ESP6500AA AF: 0.179 AC: 787

ESP6500EA AF: 0.143 AC: 1221

ExAC AF: 0.137 AC: 16191

Asia WGS AF: 0.183 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.088
DANN	Benign	0.76
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0027	T
PhyloP100		-4.5
Sift4G	Pathogenic	0.0	D
Vest4		0.10
GERP RS		-9.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3787430; hg19: chr20-60791422; COSMIC: COSV58048556;