rs7651620

Positions:

• chr3-11259846-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001098212.2(HRH1):​c.809G>A​(p.Gly270Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,006 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (63 hom.)
• Consequence: HRH1 NM_001098212.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.451

Genes affected

HRH1 (HGNC:5182): (histamine receptor H1) 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. The protein encoded by this gene is an integral membrane protein and belongs to the G protein-coupled receptor superfamily. It mediates the contraction of smooth muscles, the increase in capillary permeability due to contraction of terminal venules, the release of catecholamine from adrenal medulla, and neurotransmission in the central nervous system. It has been associated with multiple processes, including memory and learning, circadian rhythm, and thermoregulation. It is also known to contribute to the pathophysiology of allergic diseases such as atopic dermatitis, asthma, anaphylaxis and allergic rhinitis. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022179484).
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRH1	NM_001098212.2	c.809G>A	p.Gly270Glu	missense_variant	2/2	ENST00000431010.3	NP_001091682.1
HRH1	NM_000861.3	c.809G>A	p.Gly270Glu	missense_variant	3/3		NP_000852.1
HRH1	NM_001098211.2	c.809G>A	p.Gly270Glu	missense_variant	2/2		NP_001091681.1
HRH1	NM_001098213.2	c.809G>A	p.Gly270Glu	missense_variant	2/2		NP_001091683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRH1	ENST00000431010.3	c.809G>A	p.Gly270Glu	missense_variant	2/2	1	NM_001098212.2	ENSP00000397028	P1
HRH1	ENST00000397056.1	c.809G>A	p.Gly270Glu	missense_variant	3/3	1		ENSP00000380247	P1
HRH1	ENST00000438284.2	c.809G>A	p.Gly270Glu	missense_variant	2/2	2		ENSP00000406705	P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2174 AN: 152100 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00383 AC: 961 AN: 250874 Hom.: 25 AF XY: 0.00279 AC XY: 379 AN XY: 135622

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00153 AC: 2243 AN: 1461788 Hom.: 63 Cov.: 34 AF XY: 0.00129 AC XY: 941 AN XY: 727198

Gnomad4 AFR exome AF: 0.0545

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.00331

GnomAD4 genome AF: 0.0143 AC: 2178 AN: 152218 Hom.: 56 Cov.: 32 AF XY: 0.0134 AC XY: 1000 AN XY: 74410

Gnomad4 AFR AF: 0.0500

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00244 Hom.: 13

Bravo AF: 0.0160

ESP6500AA AF: 0.0474 AC: 209

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00450 AC: 546

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.6
DANN	Benign	0.38
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.57	.;.;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.45	N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.11
MVP		0.62
MPC		0.34
ClinPred		0.0022	T
GERP RS		-2.8
Varity_R		0.022
gMVP		0.14

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

Other links and lift over

dbSNP: rs7651620; hg19: chr3-11301532; COSMIC: COSV99081382; COSMIC: COSV99081382;