20-62216129-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007232.3(HRH3):c.1215G>A(p.Ser405=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,613,150 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (34 hom.)
• Consequence: HRH3 NM_007232.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.73

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 20-62216129-C-T is Benign according to our data. Variant chr20-62216129-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 782631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00543 (7928/1460900) while in subpopulation MID AF= 0.0281 (162/5766). AF 95% confidence interval is 0.0246. There are 34 homozygotes in gnomad4_exome. There are 3901 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH3	NM_007232.3	c.1215G>A	p.Ser405=	synonymous_variant	3/3	ENST00000340177.10
HRH3	XM_005260266.4	c.1215G>A	p.Ser405=	synonymous_variant	3/4
HRH3	XM_017027623.2	c.1173G>A	p.Ser391=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH3	ENST00000340177.10	c.1215G>A	p.Ser405=	synonymous_variant	3/3	1	NM_007232.3	P1
HRH3	ENST00000317393.10	c.975G>A	p.Ser325=	synonymous_variant	4/5	1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 721 AN: 152132 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00478 AC: 1187 AN: 248164 Hom.: 6 AF XY: 0.00475 AC XY: 638 AN XY: 134456

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00711

Gnomad ASJ exome AF: 0.00406

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00689

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00543 AC: 7928 AN: 1460900 Hom.: 34 Cov.: 30 AF XY: 0.00537 AC XY: 3901 AN XY: 726702

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00772

Gnomad4 ASJ exome AF: 0.00369

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.000359

Gnomad4 NFE exome AF: 0.00608

Gnomad4 OTH exome AF: 0.00605

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152250 Hom.: 6 Cov.: 33 AF XY: 0.00465 AC XY: 346 AN XY: 74438

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00657

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00564 Hom.: 1

Bravo AF: 0.00507

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00742

EpiControl AF: 0.00855

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	HRH3: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	3.8
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2067476; hg19: chr20-60791185;