rs3791244

Variant names:

• chr2-137974195-G-A
• rs3791244
• NM_006895.3:c.190+3978G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006895.3(HNMT):​c.190+3978G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,152 control chromosomes in the GnomAD database, including 1,458 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1458 hom., cov: 32)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0380
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 51

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3	c.190+3978G>A		intron_variant	Intron 2 of 5	ENST00000280097.5	NP_008826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.190+3978G>A		intron_variant	Intron 2 of 5	1	NM_006895.3	ENSP00000280097.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19084 AN: 152034 Hom.: 1459 Cov.: 32

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.149

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.125 AC: 19078 AN: 152152 Hom.: 1458 Cov.: 32 AF XY: 0.125 AC XY: 9272 AN XY: 74372

African (AFR) AF: 0.0492 AC: 2041 AN: 41520

American (AMR) AF: 0.113 AC: 1734 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3470

East Asian (EAS) AF: 0.114 AC: 589 AN: 5186

South Asian (SAS) AF: 0.163 AC: 787 AN: 4814

European-Finnish (FIN) AF: 0.117 AC: 1235 AN: 10588

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11440 AN: 67972

Other (OTH) AF: 0.147 AC: 310 AN: 2110

Alfa AF: 0.162 Hom.: 2468

Bravo AF: 0.120

Asia WGS AF: 0.143 AC: 498 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.65
DANN	Benign	0.24
PhyloP100		-0.038
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3791244; hg19: chr2-138731765;