2-137967432-C-T

Variant names:

• chr2-137967432-C-T
• rs1471003
• ENST00000280096.5:c.*317C>T

Variant summary

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

The ENST00000280096.5(HNMT):​c.*317C>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 0.975 in 274,684 control chromosomes in the GnomAD database, including 130,933 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 0.96 (70457 hom., cov: 31)
  • Exomes 𝑓: 0.99 (60476 hom.)
• Consequence: HNMT ENST00000280096.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.621
• Publications: 3 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3	c.138-2733C>T		intron_variant	Intron 1 of 5	ENST00000280097.5	NP_008826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.138-2733C>T		intron_variant	Intron 1 of 5	1	NM_006895.3	ENSP00000280097.3

Frequencies

GnomAD3 genomes AF: 0.960 AC: 146112 AN: 152166 Hom.: 70410 Cov.: 31

Gnomad AFR AF: 0.864

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.970

GnomAD4 exome AF: 0.994 AC: 121630 AN: 122400 Hom.: 60476 Cov.: 0 AF XY: 0.994 AC XY: 62179 AN XY: 62536

African (AFR) AF: 0.871 AC: 3666 AN: 4208

American (AMR) AF: 0.985 AC: 4019 AN: 4080

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4882 AN: 4882

East Asian (EAS) AF: 1.00 AC: 9722 AN: 9722

South Asian (SAS) AF: 0.999 AC: 3200 AN: 3202

European-Finnish (FIN) AF: 1.00 AC: 7021 AN: 7022

Middle Eastern (MID) AF: 0.991 AC: 630 AN: 636

European-Non Finnish (NFE) AF: 0.999 AC: 79921 AN: 79970

Other (OTH) AF: 0.987 AC: 8569 AN: 8678

GnomAD4 genome AF: 0.960 AC: 146217 AN: 152284 Hom.: 70457 Cov.: 31 AF XY: 0.962 AC XY: 71605 AN XY: 74462

African (AFR) AF: 0.864 AC: 35895 AN: 41526

American (AMR) AF: 0.979 AC: 14987 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4823 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67990 AN: 68034

Other (OTH) AF: 0.970 AC: 2053 AN: 2116

Alfa AF: 0.979 Hom.: 129704

Bravo AF: 0.954

Asia WGS AF: 0.993 AC: 3455 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.21
DANN	Benign	0.36
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1471003; hg19: chr2-138725002;