rs4954941

Positions:

• chr2-138012397-G-A

Variant summary

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

The NM_006895.3(HNMT):​c.524-1378G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 151,944 control chromosomes in the GnomAD database, including 3,756 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 0.21 (3756 hom., cov: 32)
• Consequence: HNMT NM_006895.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.102

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]

LOC107985948 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNMT	NM_006895.3	c.524-1378G>A		intron_variant		ENST00000280097.5	NP_008826.1
LOC107985948	XR_001739719.2	n.239-4601C>T		intron_variant, non_coding_transcript_variant
HNMT	XM_011511064.3	c.146-1378G>A		intron_variant			XP_011509366.1
HNMT	XM_017003948.2	c.422-1378G>A		intron_variant			XP_016859437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.524-1378G>A		intron_variant		1	NM_006895.3	ENSP00000280097	P1
HNMT	ENST00000410115.5	c.524-1378G>A		intron_variant		5		ENSP00000386940	P1
HNMT	ENST00000485653.1	n.456-1378G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32390 AN: 151824 Hom.: 3753 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.213 AC: 32421 AN: 151944 Hom.: 3756 Cov.: 32 AF XY: 0.218 AC XY: 16183 AN XY: 74238

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.233

Alfa AF: 0.215 Hom.: 444

Bravo AF: 0.212

Asia WGS AF: 0.328 AC: 1136 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.81
DANN	Benign	0.42

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: rs4954941; hg19: chr2-138769967;