18-24468817-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97
Variant links:
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]

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ACMG classification

Classification made for transcript

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
HRH4NM_021624.4 linkc.223C>T p.His75Tyr missense_variant Exon 2 of 3 ENST00000256906.5 NP_067637.2 Q9H3N8-1
HRH4NM_001143828.2 linkc.193+7896C>T intron_variant Intron 1 of 1 NP_001137300.1 Q9H3N8-2
HRH4NM_001160166.2 linkc.193+7896C>T intron_variant Intron 1 of 1 NP_001153638.1 Q9H3N8B2KJ49

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HRH4ENST00000256906.5 linkc.223C>T p.His75Tyr missense_variant Exon 2 of 3 1 NM_021624.4 ENSP00000256906.4 Q9H3N8-1
HRH4ENST00000426880.2 linkc.193+7896C>T intron_variant Intron 1 of 1 1 ENSP00000402526.2 Q9H3N8-2

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
LINK: link

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; API