Genetic Variant HNMT:p.Val102Ala (chr2-138002070-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006895.3(HNMT):c.305T>C(p.Val102Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,425,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HNMT
NM_006895.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.10

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3 link	c.305T>C	p.Val102Ala	missense_variant	Exon 4 of 6	ENST00000280097.5	NP_008826.1	P50135-1
HNMT	XM_017003948.2 link	c.203T>C	p.Val68Ala	missense_variant	Exon 4 of 6		XP_016859437.1
HNMT	XM_017003949.3 link	c.305T>C	p.Val102Ala	missense_variant	Exon 4 of 5		XP_016859438.1	B4DWC1
HNMT	XM_011511064.3 link	c.-74T>C		5_prime_UTR_variant	Exon 3 of 5		XP_011509366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HNMT	ENST00000280097.5 link	c.305T>C	p.Val102Ala	missense_variant	Exon 4 of 6	1	NM_006895.3	ENSP00000280097.3	P50135-1
HNMT	ENST00000410115.5 link	c.305T>C	p.Val102Ala	missense_variant	Exon 5 of 7	5		ENSP00000386940.1	P50135-1
HNMT	ENST00000467390.5 link	n.317T>C		non_coding_transcript_exon_variant	Exon 4 of 5	2
HNMT	ENST00000485653.1 link	n.237T>C		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000437

AC:

AN:

228708

Hom.:

AF XY:

0.00

AC XY:

AN XY:

123728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000602

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1425386

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.305T>C (p.V102A) alteration is located in exon 4 (coding exon 4) of the HNMT gene. This alteration results from a T to C substitution at nucleotide position 305, causing the valine (V) at amino acid position 102 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.69

MutPred

0.71

Gain of disorder (P = 0.0382);Gain of disorder (P = 0.0382);

MVP

0.42

MPC

0.41

ClinPred

0.99

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over