2-138016068-C-T

Variant names:

• chr2-138016068-C-T
• rs1455158
• NM_006895.3:c.*1938C>T

Variant summary

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

The NM_006895.3(HNMT):​c.*1938C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 151,936 control chromosomes in the GnomAD database, including 9,005 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 0.31 (9005 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: HNMT NM_006895.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.630
• Publications: 11 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309081 (HGNC:):

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 (AFR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006895.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	NM_006895.3	MANE Select	c.*1938C>T		3_prime_UTR	Exon 6 of 6	NP_008826.1	P50135-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	ENST00000280097.5	TSL:1 MANE Select	c.*1938C>T		3_prime_UTR	Exon 6 of 6	ENSP00000280097.3	P50135-1
	HNMT	ENST00000894492.1		c.*1938C>T		3_prime_UTR	Exon 5 of 5	ENSP00000564551.1
	ENSG00000309081	ENST00000838313.1		n.229-8272G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47713 AN: 151816 Hom.: 8982 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.312

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.315 AC: 47803 AN: 151936 Hom.: 9005 Cov.: 32 AF XY: 0.317 AC XY: 23540 AN XY: 74256

African (AFR) AF: 0.521 AC: 21574 AN: 41444

American (AMR) AF: 0.330 AC: 5032 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 952 AN: 3470

East Asian (EAS) AF: 0.273 AC: 1406 AN: 5158

South Asian (SAS) AF: 0.305 AC: 1470 AN: 4814

European-Finnish (FIN) AF: 0.255 AC: 2691 AN: 10566

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13654 AN: 67934

Other (OTH) AF: 0.314 AC: 662 AN: 2110

Alfa AF: 0.240 Hom.: 20848

Bravo AF: 0.329

Asia WGS AF: 0.350 AC: 1216 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.65
DANN	Benign	0.29
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1455158; hg19: chr2-138773638;