3-11259094-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001098212.2(HRH1):c.57G>C(p.Lys19Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,613,478 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: HRH1 NM_001098212.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.85

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037067235).
• BP6: Variant 3-11259094-G-C is Benign according to our data. Variant chr3-11259094-G-C is described in ClinVar as [Benign]. Clinvar id is 790260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH1	NM_001098212.2	c.57G>C	p.Lys19Asn	missense_variant	2/2	ENST00000431010.3
HRH1	NM_000861.3	c.57G>C	p.Lys19Asn	missense_variant	3/3
HRH1	NM_001098211.2	c.57G>C	p.Lys19Asn	missense_variant	2/2
HRH1	NM_001098213.2	c.57G>C	p.Lys19Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH1	ENST00000431010.3	c.57G>C	p.Lys19Asn	missense_variant	2/2	1	NM_001098212.2	P1
HRH1	ENST00000397056.1	c.57G>C	p.Lys19Asn	missense_variant	3/3	1		P1
HRH1	ENST00000438284.2	c.57G>C	p.Lys19Asn	missense_variant	2/2	2		P1
HRH1	ENST00000413416.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152204 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00409 AC: 1022 AN: 250154 Hom.: 3 AF XY: 0.00431 AC XY: 583 AN XY: 135146

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00451

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00718

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00470 AC: 6871 AN: 1461156 Hom.: 22 Cov.: 34 AF XY: 0.00461 AC XY: 3353 AN XY: 726918

Gnomad4 AFR exome AF: 0.000808

Gnomad4 AMR exome AF: 0.00299

Gnomad4 ASJ exome AF: 0.00560

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00742

Gnomad4 NFE exome AF: 0.00521

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152322 Hom.: 2 Cov.: 31 AF XY: 0.00423 AC XY: 315 AN XY: 74488

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00904

Gnomad4 NFE AF: 0.00545

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00519 Hom.: 3

Bravo AF: 0.00383

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00430 AC: 522

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00694

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 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.39	N
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.70	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.65	P;P;P
Vest4		0.069
MutPred		0.12		Loss of ubiquitination at K19 (P = 0.0047);Loss of ubiquitination at K19 (P = 0.0047);Loss of ubiquitination at K19 (P = 0.0047);
MVP		0.60
MPC		0.37
ClinPred		0.019	T
GERP RS		5.0
Varity_R		0.18
gMVP		0.21

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: rs2067466; hg19: chr3-11300780;