rs11662595

Positions:

• chr18-24477006-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021624.4(HRH4):​c.617A>G​(p.His206Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0864 in 1,614,096 control chromosomes in the GnomAD database, including 6,612 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.076 (584 hom., cov: 33)
  • Exomes 𝑓: 0.087 (6028 hom.)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028360784).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRH4	NM_021624.4	c.617A>G	p.His206Arg	missense_variant	3/3	ENST00000256906.5	NP_067637.2
HRH4	NM_001143828.2	c.353A>G	p.His118Arg	missense_variant	2/2		NP_001137300.1
HRH4	NM_001160166.2	c.*249A>G		3_prime_UTR_variant	2/2		NP_001153638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRH4	ENST00000256906.5	c.617A>G	p.His206Arg	missense_variant	3/3	1	NM_021624.4	ENSP00000256906.4
HRH4	ENST00000426880.2	c.353A>G	p.His118Arg	missense_variant	2/2	1		ENSP00000402526.2

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11604 AN: 152158 Hom.: 582 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0822

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0943

Gnomad OTH AF: 0.0798

GnomAD3 exomes AF: 0.0864 AC: 21699 AN: 251034 Hom.: 1173 AF XY: 0.0853 AC XY: 11577 AN XY: 135646

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.0809

Gnomad EAS exome AF: 0.0314

Gnomad SAS exome AF: 0.0479

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0941

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.0874 AC: 127796 AN: 1461820 Hom.: 6028 Cov.: 33 AF XY: 0.0866 AC XY: 62944 AN XY: 727228

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.0795

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0910

Gnomad4 OTH exome AF: 0.0843

GnomAD4 genome AF: 0.0763 AC: 11612 AN: 152276 Hom.: 584 Cov.: 33 AF XY: 0.0772 AC XY: 5745 AN XY: 74442

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0822

Gnomad4 EAS AF: 0.0371

Gnomad4 SAS AF: 0.0456

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.0943

Gnomad4 OTH AF: 0.0804

Alfa AF: 0.0904 Hom.: 1279

Bravo AF: 0.0759

TwinsUK AF: 0.0960 AC: 356

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.0990 AC: 851

ExAC AF: 0.0826 AC: 10028

Asia WGS AF: 0.0540 AC: 187 AN: 3478

EpiCase AF: 0.0978

EpiControl AF: 0.101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.096
DANN	Benign	0.47
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.095	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.66	N;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.024
MPC		0.12
ClinPred		0.00030	T
GERP RS		-4.7
Varity_R		0.032
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs11662595; hg19: chr18-22056970; COSMIC: COSV56927663;