2-138002096-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_006895.3(HNMT):c.331G>A(p.Val111Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,596,370 control chromosomes in the GnomAD database, including 1 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (1 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.570

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08207643).
• BP6: Variant 2-138002096-G-A is Benign according to our data. Variant chr2-138002096-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3106369.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNMT	NM_006895.3	c.331G>A	p.Val111Ile	missense_variant	4/6	ENST00000280097.5
HNMT	XM_017003948.2	c.229G>A	p.Val77Ile	missense_variant	4/6
HNMT	XM_017003949.3	c.331G>A	p.Val111Ile	missense_variant	4/5
HNMT	XM_011511064.3	c.-48G>A		5_prime_UTR_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNMT	ENST00000280097.5	c.331G>A	p.Val111Ile	missense_variant	4/6	1	NM_006895.3	P1
HNMT	ENST00000410115.5	c.331G>A	p.Val111Ile	missense_variant	5/7	5		P1
HNMT	ENST00000467390.5	n.343G>A		non_coding_transcript_exon_variant	4/5	2
HNMT	ENST00000485653.1	n.263G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000124 AC: 3 AN: 241316 Hom.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 130474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1444222 Hom.: 1 Cov.: 29 AF XY: 0.00000836 AC XY: 6 AN XY: 717906

Gnomad4 AFR exome AF: 0.0000917

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000768

Gnomad4 SAS exome AF: 0.0000365

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000503

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

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

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Benign	0.49
DEOGEN2	Benign	0.058	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.32	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;N
MutationTaster	Benign	0.74	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;B
Vest4		0.16
MutPred		0.57		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.22
MPC		0.053
ClinPred		0.0097	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.18

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: rs779158046; hg19: chr2-138759666; COSMIC: COSV99698806;