rs765863580

Positions:

• chr2-138005175-TC-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006895.3(HNMT):​c.475del​(p.His159IlefsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 1,452,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: HNMT NM_006895.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.51

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-138005175-TC-T is Pathogenic according to our data. Variant chr2-138005175-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445774.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNMT	NM_006895.3	c.475del	p.His159IlefsTer4	frameshift_variant	5/6	ENST00000280097.5	NP_008826.1
HNMT	XM_017003948.2	c.373del	p.His125IlefsTer4	frameshift_variant	5/6		XP_016859437.1
HNMT	XM_011511064.3	c.97del	p.His33IlefsTer4	frameshift_variant	4/5		XP_011509366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.475del	p.His159IlefsTer4	frameshift_variant	5/6	1	NM_006895.3	ENSP00000280097	P1
HNMT	ENST00000410115.5	c.475del	p.His159IlefsTer4	frameshift_variant	6/7	5		ENSP00000386940	P1
HNMT	ENST00000485653.1	n.407del		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000599 AC: 15 AN: 250516 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1452462 Hom.: 0 Cov.: 27 AF XY: 0.00000691 AC XY: 5 AN XY: 723136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 10, 2022

The c.475del variant in HNMT has not previously been reported in the literature but it has been deposited in ClinVar [ClinVar ID: 445774] as Likely pathogenic. The c.475del variant is observed in 21 alleles (~0.00004% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMedFreeze 8. All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.475del variant in HNMT is located in exon 5 of this 6-exon gene, and is predicted to incorporate a premature termination codon (p.(His159IlefsTer4), which might result in either loss-of-function via nonsense mediated decay or loss of the last 129 amino acids (>10% of the protein). Based on available evidence this inherited c.475del p.(His159IlefsTer4) variant identified in HNMT is classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Apr 17, 2017

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 15, 2023

Variant summary: HNMT c.475delC (p.His159IlefsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in HNMT as causative of disease. The variant allele was found at a frequency of 6e-05 in 250516 control chromosomes (i.e., 15 heterozygotes; gnomAD v2 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.475delC in individuals affected with HNMT-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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: rs765863580; hg19: chr2-138762745;