3-11259079-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001098212.2(HRH1):c.42G>A(p.Met14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000872 in 1,611,990 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: HRH1 NM_001098212.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.83

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006652117).
• BP6: Variant 3-11259079-G-A is Benign according to our data. Variant chr3-11259079-G-A is described in ClinVar as [Benign]. Clinvar id is 733135.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH1	NM_001098212.2	c.42G>A	p.Met14Ile	missense_variant	2/2	ENST00000431010.3
HRH1	NM_000861.3	c.42G>A	p.Met14Ile	missense_variant	3/3
HRH1	NM_001098211.2	c.42G>A	p.Met14Ile	missense_variant	2/2
HRH1	NM_001098213.2	c.42G>A	p.Met14Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH1	ENST00000431010.3	c.42G>A	p.Met14Ile	missense_variant	2/2	1	NM_001098212.2	P1
HRH1	ENST00000397056.1	c.42G>A	p.Met14Ile	missense_variant	3/3	1		P1
HRH1	ENST00000438284.2	c.42G>A	p.Met14Ile	missense_variant	2/2	2		P1
HRH1	ENST00000413416.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152236 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00120 AC: 297 AN: 248438 Hom.: 1 AF XY: 0.00108 AC XY: 145 AN XY: 134340

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000651

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000815 AC: 1190 AN: 1459636 Hom.: 1 Cov.: 34 AF XY: 0.000812 AC XY: 590 AN XY: 726192

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000508

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152354 Hom.: 0 Cov.: 31 AF XY: 0.00134 AC XY: 100 AN XY: 74506

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00137 Hom.: 4

Bravo AF: 0.00180

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00101

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

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.084	T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.058	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.95	P;P;P
Vest4		0.30
MutPred		0.43		Loss of disorder (P = 0.0211);Loss of disorder (P = 0.0211);Loss of disorder (P = 0.0211);
MVP		0.74
MPC		0.34
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.24
gMVP		0.51

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: rs79314450; hg19: chr3-11300765;