18-24468817-C-T

Variant names:

• chr18-24468817-C-T
• NM_021624.4:c.223C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021624.4(HRH4):​c.223C>T​(p.His75Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

Genes affected

HRH4 (HGNC:17383): (histamine receptor H4) Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by a family of histamine receptors, which are a subset of the G-protein coupled receptor superfamily. This gene encodes a histamine receptor that is predominantly expressed in haematopoietic cells. The protein is thought to play a role in inflammation and allergy reponses. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068220615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRH4	NM_021624.4	c.223C>T	p.His75Tyr	missense_variant	Exon 2 of 3	ENST00000256906.5	NP_067637.2
HRH4	NM_001143828.2	c.193+7896C>T		intron_variant	Intron 1 of 1		NP_001137300.1
HRH4	NM_001160166.2	c.193+7896C>T		intron_variant	Intron 1 of 1		NP_001153638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRH4	ENST00000256906.5	c.223C>T	p.His75Tyr	missense_variant	Exon 2 of 3	1	NM_021624.4	ENSP00000256906.4
HRH4	ENST00000426880.2	c.193+7896C>T		intron_variant	Intron 1 of 1	1		ENSP00000402526.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223C>T (p.H75Y) alteration is located in exon 2 (coding exon 2) of the HRH4 gene. This alteration results from a C to T substitution at nucleotide position 223, causing the histidine (H) at amino acid position 75 to be replaced by a tyrosine (Y). 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	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.66
DANN	Benign	0.26
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.024
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.62		Gain of catalytic residue at H75 (P = 0.0626);
MVP		0.23
MPC		0.12
ClinPred		0.070	T
GERP RS		1.4
Varity_R		0.035
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr18-22048781;