18-24468821-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_021624.4(HRH4):c.227C>T(p.Thr76Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T76A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: HRH4 NM_021624.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.04

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031432748).
• BP6: Variant 18-24468821-C-T is Benign according to our data. Variant chr18-24468821-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2374883.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH4	NM_021624.4	c.227C>T	p.Thr76Met	missense_variant	2/3	ENST00000256906.5
HRH4	NM_001143828.2	c.193+7900C>T		intron_variant
HRH4	NM_001160166.2	c.193+7900C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH4	ENST00000256906.5	c.227C>T	p.Thr76Met	missense_variant	2/3	1	NM_021624.4	P1
HRH4	ENST00000426880.2	c.193+7900C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251152 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135742

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1461708 Hom.: 0 Cov.: 30 AF XY: 0.000120 AC XY: 87 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000953

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.032
Dann	Benign	0.67
DEOGEN2	Benign	0.032	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.031
Sift	Benign	0.13	T
Sift4G	Uncertain	0.038	D
Polyphen		0.0040	B
Vest4		0.22
MVP		0.12
MPC		0.11
ClinPred		0.044	T
GERP RS		-11
Varity_R		0.017
gMVP		0.13

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: rs146877850; hg19: chr18-22048785;