NM_021624.4:c.796A>C

Variant names:

• chr18-24477185-A-C
• NM_021624.4:c.796A>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_021624.4(HRH4):​c.796A>C​(p.Lys266Gln) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.804

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044338405).
• BP6: Variant 18-24477185-A-C is Benign according to our data. Variant chr18-24477185-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3526609.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRH4	NM_021624.4	c.796A>C	p.Lys266Gln	missense_variant	Exon 3 of 3	ENST00000256906.5	NP_067637.2
HRH4	NM_001143828.2	c.532A>C	p.Lys178Gln	missense_variant	Exon 2 of 2		NP_001137300.1
HRH4	NM_001160166.2	c.*428A>C		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.796A>C	p.Lys266Gln	missense_variant	Exon 3 of 3	1	NM_021624.4	ENSP00000256906.4
HRH4	ENST00000426880.2	c.532A>C	p.Lys178Gln	missense_variant	Exon 2 of 2	1		ENSP00000402526.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 11, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.4
DANN	Benign	0.17
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.050
Sift	Benign	0.58	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.016	B;.
Vest4		0.017
MutPred		0.33		Loss of sheet (P = 0.0181);.;
MVP		0.25
MPC		0.11
ClinPred		0.027	T
GERP RS		3.0
Varity_R		0.064
gMVP		0.11

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: chr18-22057149;