chr3-11259094-G-C

Position:

chr3-11259094-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0047 ( 22 hom. )

Consequence

HRH1
NM_001098212.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.85

Variant links:

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]

HRH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 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_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRH1	NM_001098212.2 link	c.57G>C	p.Lys19Asn	missense_variant	2/2	ENST00000431010.3	NP_001091682.1	P35367
HRH1	NM_000861.3 link	c.57G>C	p.Lys19Asn	missense_variant	3/3		NP_000852.1	P35367
HRH1	NM_001098211.2 link	c.57G>C	p.Lys19Asn	missense_variant	2/2		NP_001091681.1	P35367
HRH1	NM_001098213.2 link	c.57G>C	p.Lys19Asn	missense_variant	2/2		NP_001091683.1	P35367

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HRH1	ENST00000431010.3 link	c.57G>C	p.Lys19Asn	missense_variant	2/2	1	NM_001098212.2	ENSP00000397028.2	P35367
HRH1	ENST00000397056.1 link	c.57G>C	p.Lys19Asn	missense_variant	3/3	1		ENSP00000380247.1	P35367
HRH1	ENST00000438284.2 link	c.57G>C	p.Lys19Asn	missense_variant	2/2	2		ENSP00000406705.2	P35367
HRH1	ENST00000413416.1 link	c.*19G>C		downstream_gene_variant		4		ENSP00000392383.1	C9J2E6

Frequencies

GnomAD3 genomes

AF:

0.00384

AC:

585

AN:

152204

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00431

AC XY:

583

AN XY:

135146

show subpopulations

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.:

Cov.:

AF XY:

0.00461

AC XY:

3353

AN XY:

726918

show subpopulations

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.:

Cov.:

AF XY:

0.00423

AC XY:

315

AN XY:

74488

show subpopulations

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.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00430

AC:

522

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00694

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

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

LIST_S2

Benign

0.71

.;.;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M

PrimateAI

Benign

0.27

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over