Genetic Variant HRH4:p.Lys376Arg (chr18-24477516-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021624.4(HRH4):c.1127A>G(p.Lys376Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,453,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

HRH4
NM_021624.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

0 publications found

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]

HRH4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.124141395).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HRH4	NM_021624.4	MANE Select	c.1127A>G	p.Lys376Arg	missense	Exon 3 of 3	NP_067637.2
HRH4	NM_001143828.2		c.863A>G	p.Lys288Arg	missense	Exon 2 of 2	NP_001137300.1
HRH4	NM_001160166.2		c.*759A>G		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>G	p.Lys376Arg	missense	Exon 3 of 3	ENSP00000256906.4
	HRH4	ENST00000426880.2	TSL:1	c.863A>G	p.Lys288Arg	missense	Exon 2 of 2	ENSP00000402526.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1453404

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32950

American (AMR)

AF:

0.00

AC:

AN:

43074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25760

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.00

AC:

AN:

85648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000812

AC:

AN:

1107766

Other (OTH)

AF:

0.0000167

AC:

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.1

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.042

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.53

M_CAP

Benign

0.0039

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.3

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.3

REVEL

Benign

0.029

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.021

Vest4

0.088

MutPred

0.40

Loss of methylation at K376 (P = 0.0011)

MVP

0.25

MPC

0.084

ClinPred

0.11

GERP RS

0.94

Varity_R

0.026

gMVP

0.059

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over