chr2-137964027-C-T

Variant names:

• chr2-137964027-C-T
• rs2071048
• ENST00000410115.5:c.-141C>T

Variant summary

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

The ENST00000410115.5(HNMT):​c.-141C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 152,432 control chromosomes in the GnomAD database, including 25,857 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 0.58 (25804 hom., cov: 33)
  • Exomes 𝑓: 0.53 (53 hom.)
• Consequence: HNMT ENST00000410115.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.817
• Publications: 16 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000410115.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	ENST00000410115.5	TSL:5	c.-141C>T		5_prime_UTR	Exon 1 of 7	ENSP00000386940.1	P50135-1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88261 AN: 151928 Hom.: 25787 Cov.: 33

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.562

GnomAD4 exome AF: 0.528 AC: 204 AN: 386 Hom.: 53 Cov.: 0 AF XY: 0.540 AC XY: 109 AN XY: 202

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.500 AC: 9 AN: 18

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 4 AN: 6

East Asian (EAS) AF: 0.333 AC: 2 AN: 6

South Asian (SAS) AF: 0.438 AC: 7 AN: 16

European-Finnish (FIN) AF: 0.250 AC: 5 AN: 20

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.553 AC: 168 AN: 304

Other (OTH) AF: 0.667 AC: 8 AN: 12

GnomAD4 genome AF: 0.581 AC: 88323 AN: 152046 Hom.: 25804 Cov.: 33 AF XY: 0.578 AC XY: 42947 AN XY: 74318

African (AFR) AF: 0.560 AC: 23186 AN: 41440

American (AMR) AF: 0.645 AC: 9849 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1634 AN: 3472

East Asian (EAS) AF: 0.626 AC: 3238 AN: 5170

South Asian (SAS) AF: 0.578 AC: 2785 AN: 4822

European-Finnish (FIN) AF: 0.512 AC: 5402 AN: 10554

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40469 AN: 67988

Other (OTH) AF: 0.565 AC: 1195 AN: 2114

Alfa AF: 0.581 Hom.: 39851

Bravo AF: 0.593

Asia WGS AF: 0.586 AC: 2039 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.22
DANN	Benign	0.76
PhyloP100		-0.82
PromoterAI		0.0064	Neutral
Mutation Taster		=300/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2071048;

hg19: chr2-138721597;