chr2-137985596-G-A

Variant names:

• chr2-137985596-G-A
• rs3100725
• NM_006895.3:c.191-15322G>A

Variant summary

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

The NM_006895.3(HNMT):​c.191-15322G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 151,926 control chromosomes in the GnomAD database, including 4,934 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 0.25 (4934 hom., cov: 32)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.299 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	NM_006895.3	MANE Select	c.191-15322G>A		intron	N/A	NP_008826.1	P50135-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	ENST00000280097.5	TSL:1 MANE Select	c.191-15322G>A		intron	N/A	ENSP00000280097.3	P50135-1
	HNMT	ENST00000410115.5	TSL:5	c.191-15322G>A		intron	N/A	ENSP00000386940.1	P50135-1
	HNMT	ENST00000894494.1		c.191-15322G>A		intron	N/A	ENSP00000564553.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37755 AN: 151808 Hom.: 4926 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.249 AC: 37796 AN: 151926 Hom.: 4934 Cov.: 32 AF XY: 0.253 AC XY: 18778 AN XY: 74234

African (AFR) AF: 0.290 AC: 12008 AN: 41400

American (AMR) AF: 0.306 AC: 4679 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1090 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1301 AN: 5138

South Asian (SAS) AF: 0.274 AC: 1317 AN: 4814

European-Finnish (FIN) AF: 0.256 AC: 2710 AN: 10566

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13775 AN: 67954

Other (OTH) AF: 0.265 AC: 561 AN: 2116

Alfa AF: 0.220 Hom.: 6630

Bravo AF: 0.252

Asia WGS AF: 0.303 AC: 1052 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	6.4
DANN	Benign	0.41
PhyloP100		0.21
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: rs3100725; hg19: chr2-138743166;