chr2-138014190-A-G

Variant names:

• chr2-138014190-A-G
• rs1050891
• NM_006895.3:c.*60A>G

Variant summary

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

The NM_006895.3(HNMT):​c.*60A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,083,194 control chromosomes in the GnomAD database, including 26,466 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 (3739 hom., cov: 32)
  • Exomes 𝑓: 0.22 (22727 hom.)
• Consequence: HNMT NM_006895.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.291
• Publications: 29 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

ENSG00000309081 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• 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 rank	MANE	Protein	UniProt
HNMT	NM_006895.3	c.*60A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000280097.5	NP_008826.1
HNMT	XM_017003948.2	c.*60A>G		3_prime_UTR_variant	Exon 6 of 6		XP_016859437.1
HNMT	XM_011511064.3	c.*60A>G		3_prime_UTR_variant	Exon 5 of 5		XP_011509366.1
LOC107985948	XR_001739719.2	n.239-6394T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.*60A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_006895.3	ENSP00000280097.3
HNMT	ENST00000410115.5	c.*60A>G		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000386940.1
ENSG00000309081	ENST00000838313.1	n.229-6394T>C		intron_variant	Intron 2 of 3
HNMT	ENST00000485653.1	n.*196A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32354 AN: 151942 Hom.: 3737 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.216 AC: 201227 AN: 931134 Hom.: 22727 Cov.: 12 AF XY: 0.218 AC XY: 102721 AN XY: 470694

African (AFR) AF: 0.172 AC: 3649 AN: 21178

American (AMR) AF: 0.370 AC: 9841 AN: 26582

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 4663 AN: 17260

East Asian (EAS) AF: 0.263 AC: 9278 AN: 35312

South Asian (SAS) AF: 0.293 AC: 17108 AN: 58418

European-Finnish (FIN) AF: 0.250 AC: 11155 AN: 44634

Middle Eastern (MID) AF: 0.270 AC: 1133 AN: 4204

European-Non Finnish (NFE) AF: 0.198 AC: 134906 AN: 681772

Other (OTH) AF: 0.227 AC: 9494 AN: 41774

GnomAD4 genome AF: 0.213 AC: 32383 AN: 152060 Hom.: 3739 Cov.: 32 AF XY: 0.218 AC XY: 16178 AN XY: 74318

African (AFR) AF: 0.169 AC: 7035 AN: 41508

American (AMR) AF: 0.291 AC: 4439 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 949 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1382 AN: 5138

South Asian (SAS) AF: 0.304 AC: 1461 AN: 4812

European-Finnish (FIN) AF: 0.255 AC: 2698 AN: 10564

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13584 AN: 67978

Other (OTH) AF: 0.233 AC: 491 AN: 2110

Alfa AF: 0.207 Hom.: 10346

Bravo AF: 0.212

Asia WGS AF: 0.327 AC: 1135 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.45
PhyloP100		0.29
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs1050891; hg19: chr2-138771760; COSMIC: COSV107240516; COSMIC: COSV107240516;