3-11260082-G-C

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.1045G>C(p.Asp349His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,614,128 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (8 hom.)
• Consequence: HRH1 NM_001098212.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

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=0.004242748).
• BP6: Variant 3-11260082-G-C is Benign according to our data. Variant chr3-11260082-G-C is described in ClinVar as [Benign]. Clinvar id is 773670.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00086 (131/152252) while in subpopulation EAS AF= 0.0217 (112/5172). AF 95% confidence interval is 0.0184. There are 1 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH1	NM_001098212.2	c.1045G>C	p.Asp349His	missense_variant	2/2	ENST00000431010.3
HRH1	NM_000861.3	c.1045G>C	p.Asp349His	missense_variant	3/3
HRH1	NM_001098211.2	c.1045G>C	p.Asp349His	missense_variant	2/2
HRH1	NM_001098213.2	c.1045G>C	p.Asp349His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH1	ENST00000431010.3	c.1045G>C	p.Asp349His	missense_variant	2/2	1	NM_001098212.2	P1
HRH1	ENST00000397056.1	c.1045G>C	p.Asp349His	missense_variant	3/3	1		P1
HRH1	ENST00000438284.2	c.1045G>C	p.Asp349His	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes AF: 0.000861 AC: 131 AN: 152134 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00171 AC: 430 AN: 251326 Hom.: 5 AF XY: 0.00157 AC XY: 213 AN XY: 135838

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0221

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000456 AC: 666 AN: 1461876 Hom.: 8 Cov.: 34 AF XY: 0.000429 AC XY: 312 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0127

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74432

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0217

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000464 Hom.: 1

Bravo AF: 0.000824

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Jun 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.092	T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	0.84	D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.061	T;T;T
Polyphen		0.93	P;P;P
Vest4		0.23
MVP		0.88
MPC		0.82
ClinPred		0.056	T
GERP RS		6.1
Varity_R		0.079
gMVP		0.45

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: rs189287776; hg19: chr3-11301768;