3-11260014-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001098212.2(HRH1):c.977G>A(p.Arg326Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,112 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (13 hom.)
• Consequence: HRH1 NM_001098212.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.99

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036764145).
• BP6: Variant 3-11260014-G-A is Benign according to our data. Variant chr3-11260014-G-A is described in ClinVar as [Benign]. Clinvar id is 708387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00567 (863/152236) while in subpopulation AFR AF= 0.0184 (763/41528). AF 95% confidence interval is 0.0173. There are 7 homozygotes in gnomad4. There are 434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH1	NM_001098212.2	c.977G>A	p.Arg326Gln	missense_variant	2/2	ENST00000431010.3
HRH1	NM_000861.3	c.977G>A	p.Arg326Gln	missense_variant	3/3
HRH1	NM_001098211.2	c.977G>A	p.Arg326Gln	missense_variant	2/2
HRH1	NM_001098213.2	c.977G>A	p.Arg326Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH1	ENST00000431010.3	c.977G>A	p.Arg326Gln	missense_variant	2/2	1	NM_001098212.2	P1
HRH1	ENST00000397056.1	c.977G>A	p.Arg326Gln	missense_variant	3/3	1		P1
HRH1	ENST00000438284.2	c.977G>A	p.Arg326Gln	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 862 AN: 152118 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00173 AC: 434 AN: 251296 Hom.: 6 AF XY: 0.00134 AC XY: 182 AN XY: 135812

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000771 AC: 1127 AN: 1461876 Hom.: 13 Cov.: 34 AF XY: 0.000707 AC XY: 514 AN XY: 727236

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00567 AC: 863 AN: 152236 Hom.: 7 Cov.: 32 AF XY: 0.00583 AC XY: 434 AN XY: 74430

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00177 Hom.: 50

Bravo AF: 0.00646

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	10
Dann	Benign	0.086
DEOGEN2	Benign	0.042	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0019	N
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.53	N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.072
MVP		0.56
MPC		0.30
ClinPred		0.0026	T
GERP RS		3.5
Varity_R		0.014
gMVP		0.12

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: rs74840800; hg19: chr3-11301700;