rs11665084

Variant names:

• chr18-24476802-C-T
• rs11665084
• NM_021624.4:c.413C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HRH4	NM_021624.4	c.413C>T	p.Ala138Val	missense_variant	Exon 3 of 3	ENST00000256906.5	NP_067637.2
HRH4	NM_001160166.2	c.*45C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001153638.1
HRH4	NM_001143828.2	c.194-45C>T		intron_variant	Intron 1 of 1		NP_001137300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRH4	ENST00000256906.5	c.413C>T	p.Ala138Val	missense_variant	Exon 3 of 3	1	NM_021624.4	ENSP00000256906.4
HRH4	ENST00000426880.2	c.194-45C>T		intron_variant	Intron 1 of 1	1		ENSP00000402526.2

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

GnomAD2 exomes AF: 0.0836 AC: 21010 AN: 251300 AF XY: 0.0825

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 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 AC: 639 AN: 33476

Gnomad4 AMR exome AF: 0.127 AC: 5693 AN: 44722

Gnomad4 ASJ exome AF: 0.0771 AC: 2014 AN: 26134

Gnomad4 EAS exome AF: 0.0429 AC: 1705 AN: 39698

Gnomad4 SAS exome AF: 0.0419 AC: 3612 AN: 86252

Gnomad4 FIN exome AF: 0.113 AC: 6023 AN: 53418

Gnomad4 NFE exome AF: 0.0897 AC: 99765 AN: 1111672

Gnomad4 Remaining exome AF: 0.0802 AC: 4845 AN: 60386

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 AC: 0.022736 AN: 0.022736

Gnomad4 AMR AF: 0.101 AC: 0.101439 AN: 0.101439

Gnomad4 ASJ AF: 0.0799 AC: 0.0799192 AN: 0.0799192

Gnomad4 EAS AF: 0.0380 AC: 0.0380015 AN: 0.0380015

Gnomad4 SAS AF: 0.0399 AC: 0.0399002 AN: 0.0399002

Gnomad4 FIN AF: 0.123 AC: 0.123461 AN: 0.123461

Gnomad4 NFE AF: 0.0926 AC: 0.0926481 AN: 0.0926481

Gnomad4 OTH AF: 0.0728 AC: 0.0728477 AN: 0.0728477

Alfa AF: 0.0847 Hom.: 2266

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
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
Mutation Taster		=78/22	polymorphism (auto)

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; COSMIC: COSV107220990;