chr2-138002106-C-T

Variant names:

• chr2-138002106-C-T
• NM_006895.3:c.341C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006895.3(HNMT):​c.341C>T​(p.Ala114Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.352405).

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.341C>T	p.Ala114Val	missense	Exon 4 of 6	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.341C>T	p.Ala114Val	missense	Exon 4 of 6	ENSP00000280097.3	P50135-1
	HNMT	ENST00000410115.5	TSL:5	c.341C>T	p.Ala114Val	missense	Exon 5 of 7	ENSP00000386940.1	P50135-1
	HNMT	ENST00000894494.1		c.341C>T	p.Ala114Val	missense	Exon 4 of 6	ENSP00000564553.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448114 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 719966

African (AFR) AF: 0.00 AC: 0 AN: 32896

American (AMR) AF: 0.00 AC: 0 AN: 43034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39218

South Asian (SAS) AF: 0.00 AC: 0 AN: 83088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105596

Other (OTH) AF: 0.00 AC: 0 AN: 59740

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.032
Sift	Benign	0.072	T
Sift4G	Benign	0.23	T
Polyphen		0.73	P
Vest4		0.18
MutPred		0.36		Gain of sheet (P = 0.039)
MVP		0.52
MPC		0.062
ClinPred		0.60	D
GERP RS		4.1
Varity_R		0.15
gMVP		0.26
Mutation Taster		=82/18	polymorphism

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

hg19: chr2-138759676;