Genetic Variant NM_006895.3:c.331G>C (chr2-138002096-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006895.3(HNMT):c.331G>C(p.Val111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. V111I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HNMT
NM_006895.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.570

Publications

0 publications found

Variant links:

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

HNMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2454493).

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.331G>C	p.Val111Leu	missense	Exon 4 of 6	NP_008826.1	P50135-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNMT	ENST00000280097.5	TSL:1 MANE Select	c.331G>C	p.Val111Leu	missense	Exon 4 of 6	ENSP00000280097.3	P50135-1
HNMT	ENST00000410115.5	TSL:5	c.331G>C	p.Val111Leu	missense	Exon 5 of 7	ENSP00000386940.1	P50135-1
HNMT	ENST00000894494.1		c.331G>C	p.Val111Leu	missense	Exon 4 of 6	ENSP00000564553.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32724

American (AMR)

AF:

0.00

AC:

AN:

42516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25578

East Asian (EAS)

AF:

0.00

AC:

AN:

39072

South Asian (SAS)

AF:

0.00

AC:

AN:

82092

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103978

Other (OTH)

AF:

0.00

AC:

AN:

59584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.011

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.57

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.0

REVEL

Benign

0.079

Sift

Uncertain

0.017

Sift4G

Uncertain

0.032

Polyphen

0.084

Vest4

0.43

MutPred

0.59

Loss of methylation at K112 (P = 0.0396)

MVP

0.22

MPC

0.084

ClinPred

0.89

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.43

Mutation Taster

=76/24

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over