Genetic Variant HRH1:c.-35-6379T>C (chr3-11252624-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001098212.2(HRH1):c.-35-6379T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 151,996 control chromosomes in the GnomAD database, including 23,990 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.55 ( 23990 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

HRH1
NM_001098212.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.968

Publications

11 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HRH1	NM_001098212.2 link	c.-35-6379T>C	intron_variant	Intron 1 of 1	ENST00000431010.3	NP_001091682.1	P35367
HRH1	NM_001098211.2 link	c.-35-6379T>C	intron_variant	Intron 1 of 1		NP_001091681.1	P35367
HRH1	NM_001098213.2 link	c.-35-6379T>C	intron_variant	Intron 1 of 1		NP_001091683.1	P35367
HRH1	NM_000861.3 link	c.-266T>C	upstream_gene_variant			NP_000852.1	P35367

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HRH1	ENST00000431010.3 link	c.-35-6379T>C	intron_variant	Intron 1 of 1	1	NM_001098212.2	ENSP00000397028.2	P35367
HRH1	ENST00000438284.2 link	c.-35-6379T>C	intron_variant	Intron 1 of 1	2		ENSP00000406705.2	P35367
HRH1	ENST00000413416.1 link	c.-35-6379T>C	intron_variant	Intron 1 of 1	4		ENSP00000392383.1	C9J2E6
HRH1	ENST00000397056.1 link	c.-266T>C	upstream_gene_variant		1		ENSP00000380247.1	P35367

Frequencies

GnomAD3 genomes

AF:

0.547

AC:

83030

AN:

151876

Hom.:

23986

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.570

Gnomad AMR

AF:

0.486

Gnomad ASJ

AF:

0.553

Gnomad EAS

AF:

0.660

Gnomad SAS

AF:

0.525

Gnomad FIN

AF:

0.643

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.655

Gnomad OTH

AF:

0.564

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.546

AC:

83063

AN:

151994

Hom.:

23990

Cov.:

AF XY:

0.544

AC XY:

40398

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.352

AC:

14597

AN:

41440

American (AMR)

AF:

0.485

AC:

7413

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

1918

AN:

3466

East Asian (EAS)

AF:

0.660

AC:

3414

AN:

5174

South Asian (SAS)

AF:

0.525

AC:

2530

AN:

4822

European-Finnish (FIN)

AF:

0.643

AC:

6785

AN:

10550

Middle Eastern (MID)

AF:

0.602

AC:

177

AN:

294

European-Non Finnish (NFE)

AF:

0.655

AC:

44508

AN:

67952

Other (OTH)

AF:

0.568

AC:

1202

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1838

3676

5513

7351

9189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.572

Hom.:

3985

Bravo

AF:

0.530

Asia WGS

AF:

0.583

AC:

2027

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.8

(source)

DANN

Benign

0.49

PhyloP100

-0.97

PromoterAI

0.023

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over