NM_021624.4:c.523C>G

Variant names:

• chr18-24476912-C-G
• NM_021624.4:c.523C>G

Variant summary

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

The NM_021624.4(HRH4):​c.523C>G​(p.Leu175Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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=0.13298726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRH4	NM_021624.4	c.523C>G	p.Leu175Val	missense_variant	Exon 3 of 3	ENST00000256906.5	NP_067637.2
HRH4	NM_001143828.2	c.259C>G	p.Leu87Val	missense_variant	Exon 2 of 2		NP_001137300.1
HRH4	NM_001160166.2	c.*155C>G		3_prime_UTR_variant	Exon 2 of 2		NP_001153638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRH4	ENST00000256906.5	c.523C>G	p.Leu175Val	missense_variant	Exon 3 of 3	1	NM_021624.4	ENSP00000256906.4
HRH4	ENST00000426880.2	c.259C>G	p.Leu87Val	missense_variant	Exon 2 of 2	1		ENSP00000402526.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523C>G (p.L175V) alteration is located in exon 3 (coding exon 3) of the HRH4 gene. This alteration results from a C to G substitution at nucleotide position 523, causing the leucine (L) at amino acid position 175 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.8
DANN	Benign	0.88
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.084
Sift	Benign	0.039	D;T
Sift4G	Benign	0.063	T;D
Polyphen		0.013	B;.
Vest4		0.067
MutPred		0.48		Gain of helix (P = 0.2059);.;
MVP		0.31
MPC		0.13
ClinPred		0.086	T
GERP RS		-3.9
Varity_R		0.14
gMVP		0.17

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: chr18-22056876;