rs1801105

chr2-138002079-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006895.3(HNMT):c.314C>T(p.Thr105Ile) variant causes a missense change. The variant allele was found at a frequency of 0.103 in 1,585,920 control chromosomes in the GnomAD database, including 9,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (732 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8456 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016437471).
• BP6: Variant 2-138002079-C-T is Benign according to our data. Variant chr2-138002079-C-T is described in ClinVar as [Benign]. Clinvar id is 5160.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNMT	NM_006895.3	c.314C>T	p.Thr105Ile	missense_variant	4/6	ENST00000280097.5
HNMT	XM_017003948.2	c.212C>T	p.Thr71Ile	missense_variant	4/6
HNMT	XM_017003949.3	c.314C>T	p.Thr105Ile	missense_variant	4/5
HNMT	XM_011511064.3	c.-65C>T		5_prime_UTR_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNMT	ENST00000280097.5	c.314C>T	p.Thr105Ile	missense_variant	4/6	1	NM_006895.3	P1
HNMT	ENST00000410115.5	c.314C>T	p.Thr105Ile	missense_variant	5/7	5		P1
HNMT	ENST00000467390.5	n.326C>T		non_coding_transcript_exon_variant	4/5	2
HNMT	ENST00000485653.1	n.246C>T		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12821 AN: 151994 Hom.: 731 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.0342

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0848

GnomAD3 exomes AF: 0.0998 AC: 23502 AN: 235484 Hom.: 1396 AF XY: 0.102 AC XY: 12922 AN XY: 127296

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.0972

Gnomad ASJ exome AF: 0.0711

Gnomad EAS exome AF: 0.0379

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.105 AC: 150234 AN: 1433808 Hom.: 8456 Cov.: 29 AF XY: 0.105 AC XY: 74795 AN XY: 712614

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0946

Gnomad4 ASJ exome AF: 0.0758

Gnomad4 EAS exome AF: 0.0459

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.0969

GnomAD4 genome AF: 0.0843 AC: 12824 AN: 152112 Hom.: 732 Cov.: 32 AF XY: 0.0863 AC XY: 6414 AN XY: 74322

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.0868

Gnomad4 ASJ AF: 0.0812

Gnomad4 EAS AF: 0.0341

Gnomad4 SAS AF: 0.0957

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0853

Alfa AF: 0.101 Hom.: 1022

Bravo AF: 0.0733

TwinsUK AF: 0.109 AC: 403

ALSPAC AF: 0.103 AC: 397

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.105 AC: 901

ExAC AF: 0.101 AC: 12228

Asia WGS AF: 0.0800 AC: 276 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

HNMT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inherited susceptibility to asthma Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.089
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.73	P;P
Vest4		0.11
MPC		0.27
ClinPred		0.044	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.38
gMVP		0.54

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

Other links and lift over

dbSNP: rs11558538; hg19: chr2-138759649; COSMIC: COSV104381302;