2-137970170-G-A

Variant names:

• chr2-137970170-G-A
• rs767467449
• NM_006895.3:c.143G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006895.3(HNMT):​c.143G>A​(p.Gly48Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,413,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G48A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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.143G>A	p.Gly48Glu	missense	Exon 2 of 6	NP_008826.1	P50135-1
	HNMT	NM_001024075.3		c.143G>A	p.Gly48Glu	missense	Exon 2 of 3	NP_001019246.1	P50135-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	ENST00000280097.5	TSL:1 MANE Select	c.143G>A	p.Gly48Glu	missense	Exon 2 of 6	ENSP00000280097.3	P50135-1
	HNMT	ENST00000329366.8	TSL:1	c.143G>A	p.Gly48Glu	missense	Exon 2 of 3	ENSP00000333259.4	P50135-2
	HNMT	ENST00000410115.5	TSL:5	c.143G>A	p.Gly48Glu	missense	Exon 3 of 7	ENSP00000386940.1	P50135-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1413636 Hom.: 0 Cov.: 23 AF XY: 0.00000142 AC XY: 1 AN XY: 704928

African (AFR) AF: 0.00 AC: 0 AN: 32118

American (AMR) AF: 0.00 AC: 0 AN: 42274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25574

East Asian (EAS) AF: 0.00 AC: 0 AN: 39114

South Asian (SAS) AF: 0.00 AC: 0 AN: 81350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1075688

Other (OTH) AF: 0.00 AC: 0 AN: 58670

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.73		Gain of solvent accessibility (P = 0.0456)
MVP		0.80
MPC		0.43
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.78
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767467449; hg19: chr2-138727740;