chr2-138014348-A-C

Variant names:

• chr2-138014348-A-C
• rs1050900
• NM_006895.3:c.*218A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006895.3(HNMT):​c.*218A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 271,946 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HNMT NM_006895.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3	c.*218A>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000280097.5	NP_008826.1
HNMT	XM_017003948.2	c.*218A>C		3_prime_UTR_variant	Exon 6 of 6		XP_016859437.1
HNMT	XM_011511064.3	c.*218A>C		3_prime_UTR_variant	Exon 5 of 5		XP_011509366.1
LOC107985948	XR_001739719.2	n.239-6552T>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.*218A>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_006895.3	ENSP00000280097.3
ENSG00000309081	ENST00000838313.1	n.229-6552T>G		intron_variant	Intron 2 of 3
HNMT	ENST00000410115.5	c.*218A>C		downstream_gene_variant		5		ENSP00000386940.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000184 AC: 5 AN: 271946 Hom.: 0 Cov.: 0 AF XY: 0.00000720 AC XY: 1 AN XY: 138978

African (AFR) AF: 0.00 AC: 0 AN: 8824

American (AMR) AF: 0.00 AC: 0 AN: 10728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9686

East Asian (EAS) AF: 0.00 AC: 0 AN: 24724

South Asian (SAS) AF: 0.00 AC: 0 AN: 8760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1336

European-Non Finnish (NFE) AF: 0.0000292 AC: 5 AN: 170952

Other (OTH) AF: 0.00 AC: 0 AN: 17300

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.94
DANN	Benign	0.37
PhyloP100		-0.19

Splicing

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

Other links and lift over

dbSNP: rs1050900; hg19: chr2-138771918;