2-137966915-G-A

Position:

• chr2-137966915-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006895.3(HNMT):​c.137+2287G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 151,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0015 (1 hom., cov: 32)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.867

Genes affected

HNMT (HGNC:5028): (histamine N-methyltransferase) In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNMT	NM_006895.3	c.137+2287G>A		intron_variant		ENST00000280097.5	NP_008826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.137+2287G>A		intron_variant		1	NM_006895.3	ENSP00000280097	P1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 233 AN: 151676 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000657

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00144

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00153 AC: 232 AN: 151794 Hom.: 1 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74192

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000656

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00155

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inherited susceptibility to asthma;C4225220:Intellectual disability, autosomal recessive 51 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 10, 2022

The c.137+2287G>A variant in HNMT has not previously been reported in the literature or public variant repositories (ClinVar and LOVD). The c.137+2287G>A variantis observed in 494 alleles (~0.0015% minor allele frequency with 1 homozygote) in population databases (gnomAD v3.1.2 and TOPMed Freeze 8), with >1% minor allele frequency in two subpopulations. The c.137+2287G>A variant is located in intron 1 of this 5-exon gene, and is moderately predicted to affect mRNA splicing (splice AI=0.57 for acceptor gain, 0.27 for acceptor loss), which might result in exon skipping or full/partial intron retention and lead to loss-of-function via nonsense mediated decay; however, there are no functional studies to support or refute these predictions. Based on available evidence this inherited c.137+2287G>A variant identified in HNMT is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.74
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.64		Position offset: 2
DS_DG_spliceai		0.20		Position offset: 50

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs186485844; hg19: chr2-138724485;