2-138002090-G-A

Position:

chr2-138002090-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006895.3(HNMT):c.325G>A(p.Glu109Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,593,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

HNMT
NM_006895.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.69

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010490447).

BP6

Variant 2-138002090-G-A is Benign according to our data. Variant chr2-138002090-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 721467.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HNMT	NM_006895.3 linkuse as main transcript	c.325G>A	p.Glu109Lys	missense_variant	4/6	ENST00000280097.5	NP_008826.1
HNMT	XM_017003948.2 linkuse as main transcript	c.223G>A	p.Glu75Lys	missense_variant	4/6		XP_016859437.1
HNMT	XM_017003949.3 linkuse as main transcript	c.325G>A	p.Glu109Lys	missense_variant	4/5		XP_016859438.1
HNMT	XM_011511064.3 linkuse as main transcript	c.-54G>A		5_prime_UTR_variant	3/5		XP_011509366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5 linkuse as main transcript	c.325G>A	p.Glu109Lys	missense_variant	4/6	1	NM_006895.3	ENSP00000280097	P1	P50135-1
HNMT	ENST00000410115.5 linkuse as main transcript	c.325G>A	p.Glu109Lys	missense_variant	5/7	5		ENSP00000386940	P1	P50135-1
HNMT	ENST00000467390.5 linkuse as main transcript	n.337G>A		non_coding_transcript_exon_variant	4/5	2
HNMT	ENST00000485653.1 linkuse as main transcript	n.257G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000544

AC:

130

AN:

239066

Hom.:

AF XY:

0.000681

AC XY:

AN XY:

129264

show subpopulations

Gnomad AFR exome

AF:

0.0000640

Gnomad AMR exome

AF:

0.0000638

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.00367

Gnomad FIN exome

AF:

0.000513

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000385

AC:

555

AN:

1440918

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

386

AN XY:

716202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000239

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000512

Gnomad4 SAS exome

AF:

0.00451

Gnomad4 FIN exome

AF:

0.000699

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.000404

GnomAD4 genome

AF:

0.000296

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000651

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal recessive 51

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.041

T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.96

L;L

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.035

Sift

Benign

0.24

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0010

B;B

Vest4

0.21

MVP

0.37

MPC

0.068

ClinPred

0.012

GERP RS

3.0

Varity_R

0.23

gMVP

0.36

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