NM_006895.3:c.524-1378G>A

Variant names:

• chr2-138012397-G-A
• rs4954941
• NM_006895.3:c.524-1378G>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.524-1378G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 151,944 control chromosomes in the GnomAD database, including 3,756 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 0.21 (3756 hom., cov: 32)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102
• Publications: 1 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

ENSG00000309081 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 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.524-1378G>A		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.524-1378G>A		intron	N/A	ENSP00000280097.3
	HNMT	ENST00000410115.5	TSL:5	c.524-1378G>A		intron	N/A	ENSP00000386940.1
	HNMT	ENST00000485653.1	TSL:5	n.456-1378G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32390 AN: 151824 Hom.: 3753 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.213 AC: 32421 AN: 151944 Hom.: 3756 Cov.: 32 AF XY: 0.218 AC XY: 16183 AN XY: 74238

African (AFR) AF: 0.170 AC: 7052 AN: 41474

American (AMR) AF: 0.291 AC: 4436 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 950 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1383 AN: 5144

South Asian (SAS) AF: 0.304 AC: 1468 AN: 4824

European-Finnish (FIN) AF: 0.255 AC: 2685 AN: 10546

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.200 AC: 13612 AN: 67924

Other (OTH) AF: 0.233 AC: 489 AN: 2100

Alfa AF: 0.213 Hom.: 457

Bravo AF: 0.212

Asia WGS AF: 0.328 AC: 1136 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.81
DANN	Benign	0.42
PhyloP100		-0.10
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: rs4954941; hg19: chr2-138769967;