Genetic Variant NM_021624.4:c.20C>A (chr18-24460748-C-A) – 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.20C>A(p.Thr7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,368,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T7I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

HRH4
NM_021624.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.65

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=0.20665827).

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	UniProt
HRH4	NM_021624.4	MANE Select	c.20C>A	p.Thr7Lys	missense	Exon 1 of 3	NP_067637.2
HRH4	NM_001143828.2		c.20C>A	p.Thr7Lys	missense	Exon 1 of 2	NP_001137300.1	Q9H3N8-2
HRH4	NM_001160166.2		c.20C>A	p.Thr7Lys	missense	Exon 1 of 2	NP_001153638.1	B2KJ49

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRH4	ENST00000256906.5	TSL:1 MANE Select	c.20C>A	p.Thr7Lys	missense	Exon 1 of 3	ENSP00000256906.4	Q9H3N8-1
	HRH4	ENST00000426880.2	TSL:1	c.20C>A	p.Thr7Lys	missense	Exon 1 of 2	ENSP00000402526.2	Q9H3N8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1368086

Hom.:

Cov.:

AF XY:

0.00000447

AC XY:

AN XY:

670768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31918

American (AMR)

AF:

0.00

AC:

AN:

39938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24040

East Asian (EAS)

AF:

0.00

AC:

AN:

38150

South Asian (SAS)

AF:

0.00

AC:

AN:

70222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

1051624

Other (OTH)

AF:

0.00

AC:

AN:

55902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.097

Eigen

Benign

-0.025

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.47

M_CAP

Benign

0.0076

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.55

PhyloP100

2.6

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

REVEL

Benign

0.16

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.056

Polyphen

0.96

Vest4

0.41

MutPred

0.33

Gain of ubiquitination at T7 (P = 0.0082)

MVP

0.65

MPC

0.25

ClinPred

0.42

GERP RS

5.9

PromoterAI

0.00010

Neutral

(source)

Varity_R

0.17

gMVP

0.11

Mutation Taster

=67/33

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