rs17583889

Positions:

• chr2-137988469-C-A
• chr2-137988469-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006895.3(HNMT):​c.191-12449C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,060 control chromosomes in the GnomAD database, including 1,651 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 (1651 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.235

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNMT	NM_006895.3	c.191-12449C>A		intron_variant		ENST00000280097.5	NP_008826.1
HNMT	XM_011511064.3	c.-188-12449C>A		intron_variant			XP_011509366.1
HNMT	XM_017003948.2	c.89-12449C>A		intron_variant			XP_016859437.1
HNMT	XM_017003949.3	c.191-12449C>A		intron_variant			XP_016859438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.191-12449C>A		intron_variant		1	NM_006895.3	ENSP00000280097	P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20416 AN: 151942 Hom.: 1653 Cov.: 32

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.154

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.134 AC: 20412 AN: 152060 Hom.: 1651 Cov.: 32 AF XY: 0.136 AC XY: 10105 AN XY: 74308

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.153

Alfa AF: 0.166 Hom.: 2387

Bravo AF: 0.124

Asia WGS AF: 0.138 AC: 480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.72

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: rs17583889; hg19: chr2-138746039;