Variant chr2-138005175-TC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 1.51

Variant links:

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]

HNMT links:

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ACMG classification

Classification made for transcript

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
HNMT	NM_006895.3 linkuse as main transcript	c.475del	p.His159IlefsTer4	frameshift_variant	5/6	ENST00000280097.5
HNMT	XM_017003948.2 linkuse as main transcript	c.373del	p.His125IlefsTer4	frameshift_variant	5/6
HNMT	XM_011511064.3 linkuse as main transcript	c.97del	p.His33IlefsTer4	frameshift_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNMT	ENST00000280097.5 linkuse as main transcript	c.475del	p.His159IlefsTer4	frameshift_variant	5/6	1	NM_006895.3	P1	P50135-1
HNMT	ENST00000410115.5 linkuse as main transcript	c.475del	p.His159IlefsTer4	frameshift_variant	6/7	5		P1	P50135-1
HNMT	ENST00000485653.1 linkuse as main transcript	n.407del		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250516

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135374

show subpopulations

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:

AN:

1452462

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723136

show subpopulations

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.:

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over