2-138002082-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006895.3(HNMT):c.317C>T(p.Ser106Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000252 in 1,586,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24743456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNMT	NM_006895.3	c.317C>T	p.Ser106Leu	missense_variant	4/6	ENST00000280097.5
HNMT	XM_017003948.2	c.215C>T	p.Ser72Leu	missense_variant	4/6
HNMT	XM_017003949.3	c.317C>T	p.Ser106Leu	missense_variant	4/5
HNMT	XM_011511064.3	c.-62C>T		5_prime_UTR_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNMT	ENST00000280097.5	c.317C>T	p.Ser106Leu	missense_variant	4/6	1	NM_006895.3	P1
HNMT	ENST00000410115.5	c.317C>T	p.Ser106Leu	missense_variant	5/7	5		P1
HNMT	ENST00000467390.5	n.329C>T		non_coding_transcript_exon_variant	4/5	2
HNMT	ENST00000485653.1	n.249C>T		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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

GnomAD3 exomes AF: 0.000102 AC: 24 AN: 235542 Hom.: 0 AF XY: 0.000118 AC XY: 15 AN XY: 127374

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.000461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.0000741

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000710

GnomAD4 exome AF: 0.0000258 AC: 37 AN: 1434646 Hom.: 0 Cov.: 29 AF XY: 0.0000309 AC XY: 22 AN XY: 713020

Gnomad4 AFR exome AF: 0.0000621

Gnomad4 AMR exome AF: 0.000392

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.000125

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74232

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 51 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 31, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.16
Sift	Benign	0.070	T;T
Sift4G	Benign	0.082	T;T
Polyphen		0.98	D;D
Vest4		0.46
MutPred		0.39		Loss of ubiquitination at K104 (P = 0.0328);Loss of ubiquitination at K104 (P = 0.0328);
MVP		0.66
MPC		0.20
ClinPred		0.17	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.28
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs755441595; hg19: chr2-138759652; COSMIC: COSV54508975;