chr2-137964113-T-C

Variant names:

• chr2-137964113-T-C
• rs11569723
• ENST00000410115.5:c.-55T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000410115.5(HNMT):​c.-55T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 160,324 control chromosomes in the GnomAD database, including 7 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 0.0065 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: HNMT ENST00000410115.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• 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=-0.52).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00653 (994/152302) while in subpopulation AFR AF = 0.0225 (935/41562). AF 95% confidence interval is 0.0213. There are 7 homozygotes in GnomAd4. There are 462 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000410115.5	c.-55T>C		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000386940.1
HNMT	ENST00000329366.8	c.-379T>C		upstream_gene_variant		1		ENSP00000333259.4

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 991 AN: 152182 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00479

GnomAD4 exome AF: 0.000499 AC: 4 AN: 8022 Hom.: 0 Cov.: 0 AF XY: 0.000469 AC XY: 2 AN XY: 4264

African (AFR) AF: 0.0159 AC: 2 AN: 126

American (AMR) AF: 0.00230 AC: 2 AN: 868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 150

East Asian (EAS) AF: 0.00 AC: 0 AN: 336

South Asian (SAS) AF: 0.00 AC: 0 AN: 810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 18

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 5000

Other (OTH) AF: 0.00 AC: 0 AN: 396

GnomAD4 genome AF: 0.00653 AC: 994 AN: 152302 Hom.: 7 Cov.: 32 AF XY: 0.00620 AC XY: 462 AN XY: 74470

African (AFR) AF: 0.0225 AC: 935 AN: 41562

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00513 Hom.: 1

Bravo AF: 0.00758

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		-0.045
PromoterAI		-0.097	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs11569723; hg19: chr2-138721683;