rs3100719

Variant names:

• chr2-138006364-G-A
• rs3100719
• NM_006895.3:c.523+1139G>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.523+1139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 151,660 control chromosomes in the GnomAD database, including 4,314 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 0.23 (4314 hom., cov: 32)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460
• Publications: 1 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

LOC107985948 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3	c.523+1139G>A		intron_variant	Intron 5 of 5	ENST00000280097.5	NP_008826.1
LOC107985948	XR_001739719.2	n.1671C>T		non_coding_transcript_exon_variant	Exon 3 of 3
HNMT	XM_017003948.2	c.421+1139G>A		intron_variant	Intron 5 of 5		XP_016859437.1
HNMT	XM_011511064.3	c.145+1139G>A		intron_variant	Intron 4 of 4		XP_011509366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.523+1139G>A		intron_variant	Intron 5 of 5	1	NM_006895.3	ENSP00000280097.3
HNMT	ENST00000410115.5	c.523+1139G>A		intron_variant	Intron 6 of 6	5		ENSP00000386940.1
HNMT	ENST00000485653.1	n.455+1139G>A		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35215 AN: 151542 Hom.: 4311 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.232 AC: 35253 AN: 151660 Hom.: 4314 Cov.: 32 AF XY: 0.237 AC XY: 17554 AN XY: 74122

African (AFR) AF: 0.236 AC: 9785 AN: 41424

American (AMR) AF: 0.299 AC: 4546 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 950 AN: 3466

East Asian (EAS) AF: 0.268 AC: 1380 AN: 5146

South Asian (SAS) AF: 0.306 AC: 1470 AN: 4804

European-Finnish (FIN) AF: 0.255 AC: 2682 AN: 10532

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13575 AN: 67788

Other (OTH) AF: 0.245 AC: 515 AN: 2100

Alfa AF: 0.226 Hom.: 507

Bravo AF: 0.233

Asia WGS AF: 0.329 AC: 1142 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.6
DANN	Benign	0.72
PhyloP100		0.46
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: rs3100719; hg19: chr2-138763934; COSMIC: COSV54507459; COSMIC: COSV54507459;