NM_006895.3:c.190+15020T>C

Variant names:

• chr2-137985237-T-C
• rs1020678
• NM_006895.3:c.190+15020T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006895.3(HNMT):​c.190+15020T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 151,650 control chromosomes in the GnomAD database, including 13,771 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (13771 hom., cov: 30)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 51

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006895.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	NM_006895.3	MANE Select	c.190+15020T>C		intron	N/A	NP_008826.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	ENST00000280097.5	TSL:1 MANE Select	c.190+15020T>C		intron	N/A	ENSP00000280097.3
	HNMT	ENST00000410115.5	TSL:5	c.190+15020T>C		intron	N/A	ENSP00000386940.1
	HNMT	ENST00000467390.5	TSL:2	n.202+15020T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.422 AC: 63910 AN: 151534 Hom.: 13757 Cov.: 30

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.448

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

GnomAD4 genome AF: 0.422 AC: 63980 AN: 151650 Hom.: 13771 Cov.: 30 AF XY: 0.427 AC XY: 31628 AN XY: 74062

African (AFR) AF: 0.474 AC: 19601 AN: 41344

American (AMR) AF: 0.438 AC: 6666 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1701 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1903 AN: 5148

South Asian (SAS) AF: 0.476 AC: 2286 AN: 4806

European-Finnish (FIN) AF: 0.432 AC: 4521 AN: 10454

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.378 AC: 25685 AN: 67898

Other (OTH) AF: 0.448 AC: 946 AN: 2110

Alfa AF: 0.397 Hom.: 8344

Bravo AF: 0.421

Asia WGS AF: 0.464 AC: 1612 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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: rs1020678; hg19: chr2-138742807;