NM_007232.3:c.1006C>T

Variant names:

• chr20-62216338-G-A
• rs1601120556
• NM_007232.3:c.1006C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007232.3(HRH3):​c.1006C>T​(p.Arg336Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HRH3 NM_007232.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.360727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007232.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRH3	NM_007232.3	MANE Select	c.1006C>T	p.Arg336Cys	missense	Exon 3 of 3	NP_009163.2	Q9Y5N1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRH3	ENST00000340177.10	TSL:1 MANE Select	c.1006C>T	p.Arg336Cys	missense	Exon 3 of 3	ENSP00000342560.5	Q9Y5N1-1
	HRH3	ENST00000317393.10	TSL:1	c.822-56C>T		intron	N/A	ENSP00000321482.7	A0A0A0MR48
	HRH3	ENST00000932927.1		c.964C>T	p.Arg322Cys	missense	Exon 3 of 3	ENSP00000602986.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450542 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 720298

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 43766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39140

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106244

Other (OTH) AF: 0.00 AC: 0 AN: 59908

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		0.15	B
Vest4		0.46
MutPred		0.51		Gain of sheet (P = 0.0166)
MVP		0.85
MPC		1.4
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.35
gMVP		0.96
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1601120556; hg19: chr20-60791394; COSMIC: COSV100420461;