rs3794261

chr12-95512827-C-Achr12-95512827-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_006838.4(METAP2):c.1095C>A(p.Thr365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0865 in 1,606,536 control chromosomes in the GnomAD database, including 6,544 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 0.094 (705 hom., cov: 31)
  • Exomes 𝑓: 0.086 (5839 hom.)
• Consequence: METAP2 NM_006838.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.356

Genes affected

METAP2 (HGNC:16672): (methionyl aminopeptidase 2) The protein encoded by this gene is a member of the methionyl aminopeptidase family. The encoded protein functions both by protecting the alpha subunit of eukaryotic initiation factor 2 from inhibitory phosphorylation and by removing the amino-terminal methionine residue from nascent proteins. Increased expression of this gene is associated with various forms of cancer, and the anti-cancer drugs fumagillin and ovalicin inhibit the protein by irreversibly binding to its active site. Inhibitors of this gene have also been shown to be effective for the treatment of obesity. A pseudogene of this gene is located on chromosome 2. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP7: Synonymous conserved (PhyloP=-0.356 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METAP2	NM_006838.4	c.1095C>A	p.Thr365=	synonymous_variant	10/11	ENST00000323666.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METAP2	ENST00000323666.10	c.1095C>A	p.Thr365=	synonymous_variant	10/11	1	NM_006838.4	P3

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14270 AN: 151914 Hom.: 709 Cov.: 31

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.0891

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0940 AC: 23510 AN: 250120 Hom.: 1305 AF XY: 0.0927 AC XY: 12537 AN XY: 135224

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0821

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.0698

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0899

Gnomad OTH exome AF: 0.0996

GnomAD4 exome AF: 0.0857 AC: 124720 AN: 1454504 Hom.: 5839 Cov.: 29 AF XY: 0.0859 AC XY: 62147 AN XY: 723828

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0824

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.0696

Gnomad4 FIN exome AF: 0.0713

Gnomad4 NFE exome AF: 0.0823

Gnomad4 OTH exome AF: 0.0949

GnomAD4 genome AF: 0.0938 AC: 14265 AN: 152032 Hom.: 705 Cov.: 31 AF XY: 0.0937 AC XY: 6958 AN XY: 74296

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0736

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.0816

Gnomad4 FIN AF: 0.0654

Gnomad4 NFE AF: 0.0891

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0916 Hom.: 1594

Bravo AF: 0.0966

Asia WGS AF: 0.155 AC: 539 AN: 3478

EpiCase AF: 0.0970

EpiControl AF: 0.101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	6.3
Dann	Benign	0.75
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

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: rs3794261; hg19: chr12-95906603; COSMIC: COSV51561430; COSMIC: COSV51561430;