18-24477516-A-T

Variant names:

• chr18-24477516-A-T
• rs77041280
• NM_021624.4:c.1127A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021624.4(HRH4):​c.1127A>T​(p.Lys376Ile) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34078813).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021624.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRH4	NM_021624.4	MANE Select	c.1127A>T	p.Lys376Ile	missense	Exon 3 of 3	NP_067637.2
	HRH4	NM_001143828.2		c.863A>T	p.Lys288Ile	missense	Exon 2 of 2	NP_001137300.1
	HRH4	NM_001160166.2		c.*759A>T		3_prime_UTR	Exon 2 of 2	NP_001153638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRH4	ENST00000256906.5	TSL:1 MANE Select	c.1127A>T	p.Lys376Ile	missense	Exon 3 of 3	ENSP00000256906.4
	HRH4	ENST00000426880.2	TSL:1	c.863A>T	p.Lys288Ile	missense	Exon 2 of 2	ENSP00000402526.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.84	P
Vest4		0.34
MutPred		0.52		Loss of methylation at K376 (P = 8e-04)
MVP		0.51
MPC		0.42
ClinPred		0.95	D
GERP RS		0.94
Varity_R		0.21
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs77041280; hg19: chr18-22057480;