3-11259279-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001098212.2(HRH1):c.242T>C(p.Met81Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HRH1 NM_001098212.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH1	NM_001098212.2	c.242T>C	p.Met81Thr	missense_variant	2/2	ENST00000431010.3
HRH1	NM_000861.3	c.242T>C	p.Met81Thr	missense_variant	3/3
HRH1	NM_001098211.2	c.242T>C	p.Met81Thr	missense_variant	2/2
HRH1	NM_001098213.2	c.242T>C	p.Met81Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH1	ENST00000431010.3	c.242T>C	p.Met81Thr	missense_variant	2/2	1	NM_001098212.2	P1
HRH1	ENST00000397056.1	c.242T>C	p.Met81Thr	missense_variant	3/3	1		P1
HRH1	ENST00000438284.2	c.242T>C	p.Met81Thr	missense_variant	2/2	2		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.242T>C (p.M81T) alteration is located in exon 2 (coding exon 1) of the HRH1 gene. This alteration results from a T to C substitution at nucleotide position 242, causing the methionine (M) at amino acid position 81 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.8	H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.72
MutPred		0.60		Gain of glycosylation at M81 (P = 0.0972);Gain of glycosylation at M81 (P = 0.0972);Gain of glycosylation at M81 (P = 0.0972);
MVP		0.94
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-11300965;