2-138002090-G-C

Variant names:

• chr2-138002090-G-C
• rs528223406
• NM_006895.3:c.325G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006895.3(HNMT):​c.325G>C​(p.Glu109Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,440,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09633091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3	c.325G>C	p.Glu109Gln	missense_variant	Exon 4 of 6	ENST00000280097.5	NP_008826.1
HNMT	XM_017003948.2	c.223G>C	p.Glu75Gln	missense_variant	Exon 4 of 6		XP_016859437.1
HNMT	XM_017003949.3	c.325G>C	p.Glu109Gln	missense_variant	Exon 4 of 5		XP_016859438.1
HNMT	XM_011511064.3	c.-54G>C		5_prime_UTR_variant	Exon 3 of 5		XP_011509366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.325G>C	p.Glu109Gln	missense_variant	Exon 4 of 6	1	NM_006895.3	ENSP00000280097.3
HNMT	ENST00000410115.5	c.325G>C	p.Glu109Gln	missense_variant	Exon 5 of 7	5		ENSP00000386940.1
HNMT	ENST00000467390.5	n.337G>C		non_coding_transcript_exon_variant	Exon 4 of 5	2
HNMT	ENST00000485653.1	n.257G>C		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000167 AC: 4 AN: 239066 Hom.: 0 AF XY: 0.0000309 AC XY: 4 AN XY: 129264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1440930 Hom.: 0 Cov.: 29 AF XY: 0.00000977 AC XY: 7 AN XY: 716212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000861

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.023
Sift	Benign	0.68	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0040	B;B
Vest4		0.20
MutPred		0.33		Gain of MoRF binding (P = 0.0205);Gain of MoRF binding (P = 0.0205);
MVP		0.50
MPC		0.062
ClinPred		0.014	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.35

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: rs528223406; hg19: chr2-138759660;