2-137964494-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_006895.3(HNMT):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000112 in 1,611,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HNMT
NM_006895.3 start_lost

Scores

2
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 12 CDS bases. Genomic position: 137964503. Lost 0.014 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNMTNM_006895.3 linkc.3G>A p.Met1? start_lost Exon 1 of 6 ENST00000280097.5 NP_008826.1 P50135-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNMTENST00000280097.5 linkc.3G>A p.Met1? start_lost Exon 1 of 6 1 NM_006895.3 ENSP00000280097.3 P50135-1

Frequencies

GnomAD3 genomes
AF:
0.0000725
AC:
11
AN:
151660
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000267
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
250350
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135286
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.00000479
AC:
7
AN:
1460082
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
4
AN XY:
726378
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000725
AC:
11
AN:
151660
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74012
show subpopulations
Gnomad4 AFR
AF:
0.000267
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterNov 02, 2023PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;.;T;.
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
.;D;D;.
M_CAP
Benign
0.075
D
MetaRNN
Uncertain
0.62
D;D;D;D
MetaSVM
Benign
-0.95
T
PROVEAN
Benign
-1.9
N;N;N;D
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.025
D;D;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.75
MutPred
0.80
Gain of catalytic residue at M1 (P = 0.019);Gain of catalytic residue at M1 (P = 0.019);Gain of catalytic residue at M1 (P = 0.019);Gain of catalytic residue at M1 (P = 0.019);
MVP
0.49
ClinPred
0.91
D
GERP RS
4.9
Varity_R
0.87
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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.

Other links and lift over

dbSNP: rs375610973; hg19: chr2-138722064; API