rs11665084

Positions:

• chr18-24476802-C-T

Variant summary

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

The NM_021624.4(HRH4):​c.413C>T​(p.Ala138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,613,688 control chromosomes in the GnomAD database, including 6,329 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.072 (538 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5791 hom.)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.841

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=0.003196627).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRH4	NM_021624.4	c.413C>T	p.Ala138Val	missense_variant	3/3	ENST00000256906.5	NP_067637.2
HRH4	NM_001160166.2	c.*45C>T		3_prime_UTR_variant	2/2		NP_001153638.1
HRH4	NM_001143828.2	c.194-45C>T		intron_variant			NP_001137300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRH4	ENST00000256906.5	c.413C>T	p.Ala138Val	missense_variant	3/3	1	NM_021624.4	ENSP00000256906	P1
HRH4	ENST00000426880.2	c.194-45C>T		intron_variant		1		ENSP00000402526

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 10995 AN: 152048 Hom.: 536 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0799

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.0403

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.0721

GnomAD3 exomes AF: 0.0836 AC: 21010 AN: 251300 Hom.: 1120 AF XY: 0.0825 AC XY: 11199 AN XY: 135810

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.0782

Gnomad EAS exome AF: 0.0312

Gnomad SAS exome AF: 0.0430

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0924

Gnomad OTH exome AF: 0.0938

GnomAD4 exome AF: 0.0855 AC: 124958 AN: 1461524 Hom.: 5791 Cov.: 33 AF XY: 0.0845 AC XY: 61436 AN XY: 727094

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.0771

Gnomad4 EAS exome AF: 0.0429

Gnomad4 SAS exome AF: 0.0419

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0897

Gnomad4 OTH exome AF: 0.0802

GnomAD4 genome AF: 0.0723 AC: 11001 AN: 152164 Hom.: 538 Cov.: 32 AF XY: 0.0733 AC XY: 5454 AN XY: 74376

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.0799

Gnomad4 EAS AF: 0.0380

Gnomad4 SAS AF: 0.0399

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.0926

Gnomad4 OTH AF: 0.0728

Alfa AF: 0.0861 Hom.: 1186

Bravo AF: 0.0705

TwinsUK AF: 0.0949 AC: 352

ALSPAC AF: 0.0890 AC: 343

ESP6500AA AF: 0.0254 AC: 112

ESP6500EA AF: 0.0976 AC: 839

ExAC AF: 0.0799 AC: 9697

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.0955

EpiControl AF: 0.0991

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.00068	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.044
Sift	Benign	0.31	T
Sift4G	Benign	0.26	T
Polyphen		0.17	B
Vest4		0.047
MPC		0.13
ClinPred		0.0091	T
GERP RS		4.9
Varity_R		0.10
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11665084; hg19: chr18-22056766;