chr2-137981259-G-C

Variant names:

• chr2-137981259-G-C
• rs376421030
• ENST00000329366.8:c.234G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001024075.3(HNMT):​c.234G>C​(p.Ser78Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,596 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. Synonymous variant affecting the same amino acid position (i.e. S78S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: HNMT NM_001024075.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024075.3. 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
	HNMT	NM_006895.3	MANE Select	c.190+11042G>C		intron	N/A	NP_008826.1	P50135-1
	HNMT	NM_001024075.3		c.234G>C	p.Ser78Ser	synonymous	Exon 3 of 3	NP_001019246.1	P50135-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNMT	ENST00000329366.8	TSL:1	c.234G>C	p.Ser78Ser	synonymous	Exon 3 of 3	ENSP00000333259.4	P50135-2
	HNMT	ENST00000280097.5	TSL:1 MANE Select	c.190+11042G>C		intron	N/A	ENSP00000280097.3	P50135-1
	HNMT	ENST00000410115.5	TSL:5	c.190+11042G>C		intron	N/A	ENSP00000386940.1	P50135-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151596 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151596 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73990

African (AFR) AF: 0.0000485 AC: 2 AN: 41204

American (AMR) AF: 0.00 AC: 0 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.1
DANN	Benign	0.52
PhyloP100		1.2
Mutation Taster		=100/0	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: rs376421030; hg19: chr2-138738829;