18-24468821-C-G

Variant summary

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

The NM_021624.4(HRH4):c.227C>G(p.Thr76Arg) 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. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76A) has been classified 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: -3.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH4	NM_021624.4	c.227C>G	p.Thr76Arg	missense_variant	2/3	ENST00000256906.5
HRH4	NM_001143828.2	c.193+7900C>G		intron_variant
HRH4	NM_001160166.2	c.193+7900C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH4	ENST00000256906.5	c.227C>G	p.Thr76Arg	missense_variant	2/3	1	NM_021624.4	P1
HRH4	ENST00000426880.2	c.193+7900C>G		intron_variant		1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.227C>G (p.T76R) alteration is located in exon 2 (coding exon 2) of the HRH4 gene. This alteration results from a C to G substitution at nucleotide position 227, causing the threonine (T) at amino acid position 76 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.064
Dann	Benign	0.59
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.050
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.035	D
Polyphen		0.065	B
Vest4		0.30
MutPred		0.47		Gain of helix (P = 0.2059);
MVP		0.12
MPC		0.13
ClinPred		0.19	T
GERP RS		-11
Varity_R		0.28
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 1

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: chr18-22048785;