rs745756308
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_006895.3(HNMT):c.623T>C(p.Leu208Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,536 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 Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
HNMT
NM_006895.3 missense
NM_006895.3 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 7.29
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 2-138013874-T-C is Pathogenic according to our data. Variant chr2-138013874-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-138013874-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNMT | NM_006895.3 | c.623T>C | p.Leu208Pro | missense_variant | 6/6 | ENST00000280097.5 | NP_008826.1 | |
HNMT | XM_017003948.2 | c.521T>C | p.Leu174Pro | missense_variant | 6/6 | XP_016859437.1 | ||
HNMT | XM_011511064.3 | c.245T>C | p.Leu82Pro | missense_variant | 5/5 | XP_011509366.1 | ||
LOC107985948 | XR_001739719.2 | n.239-6078A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNMT | ENST00000280097.5 | c.623T>C | p.Leu208Pro | missense_variant | 6/6 | 1 | NM_006895.3 | ENSP00000280097.3 | ||
HNMT | ENST00000410115.5 | c.623T>C | p.Leu208Pro | missense_variant | 7/7 | 5 | ENSP00000386940.1 | |||
HNMT | ENST00000485653.1 | n.555T>C | non_coding_transcript_exon_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250958Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135620
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461536Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727072
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, autosomal recessive 51 Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Aug 13, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 15, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 10, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of stability (P = 0.015);Loss of stability (P = 0.015);
MVP
MPC
0.48
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at