20-62216348-C-T

Variant summary

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

The NM_007232.3(HRH3):c.996G>A(p.Ser332=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,592,330 control chromosomes in the GnomAD database, including 136,962 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (15747 hom., cov: 33)
  • Exomes 𝑓: 0.41 (121215 hom.)
• Consequence: HRH3 NM_007232.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

Genes affected

HRH3 (HGNC:5184): (histamine receptor H3) Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3 and H4. This gene encodes one of the histamine receptors (H3) which belongs to the family 1 of G protein-coupled receptors. It is an integral membrane protein and can regulate neurotransmitter release. This receptor can also increase voltage-dependent calcium current in smooth muscles and innervates the blood vessels and the heart in cardiovascular system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.982573E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH3	NM_007232.3	c.996G>A	p.Ser332=	synonymous_variant	3/3	ENST00000340177.10
HRH3	XM_005260266.4	c.996G>A	p.Ser332=	synonymous_variant	3/4
HRH3	XM_017027623.2	c.954G>A	p.Ser318=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH3	ENST00000340177.10	c.996G>A	p.Ser332=	synonymous_variant	3/3	1	NM_007232.3	P1
HRH3	ENST00000317393.10	c.822-66G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68060 AN: 151942 Hom.: 15713 Cov.: 33

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.417

GnomAD3 exomes AF: 0.447 AC: 98502 AN: 220444 Hom.: 22236 AF XY: 0.443 AC XY: 53145 AN XY: 119914

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.536

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.423

GnomAD4 exome AF: 0.407 AC: 586049 AN: 1440268 Hom.: 121215 Cov.: 62 AF XY: 0.410 AC XY: 292354 AN XY: 713928

Gnomad4 AFR exome AF: 0.561

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.330

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.419

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.405

GnomAD4 genome AF: 0.448 AC: 68148 AN: 152062 Hom.: 15747 Cov.: 33 AF XY: 0.449 AC XY: 33382 AN XY: 74330

Gnomad4 AFR AF: 0.555

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.416

Alfa AF: 0.393 Hom.: 13896

Bravo AF: 0.456

TwinsUK AF: 0.389 AC: 1444

ALSPAC AF: 0.390 AC: 1502

ESP6500AA AF: 0.547 AC: 2403

ESP6500EA AF: 0.395 AC: 3387

ExAC AF: 0.426 AC: 51112

Asia WGS AF: 0.481 AC: 1671 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.21
Dann	Benign	0.80
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000080	T
MutationTaster	Benign	0.00018	P;P
Vest4		0.050
GERP RS		-9.2

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: rs3787429; hg19: chr20-60791404; COSMIC: COSV58047736;