rs3794261

Variant names:

• chr12-95512827-C-A
• rs3794261
• NM_006838.4:c.1095C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-95512827-C-A
• chr12-95512827-C-G
• chr12-95512827-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_006838.4(METAP2):​c.1095C>A​(p.Thr365Thr) 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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
METAP2	NM_006838.4	c.1095C>A	p.Thr365Thr	synonymous_variant	Exon 10 of 11	ENST00000323666.10	NP_006829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METAP2	ENST00000323666.10	c.1095C>A	p.Thr365Thr	synonymous_variant	Exon 10 of 11	1	NM_006838.4	ENSP00000325312.5

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

GnomAD2 exomes AF: 0.0940 AC: 23510 AN: 250120 AF XY: 0.0927

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 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

African (AFR) AF: 0.105 AC: 3475 AN: 33240

American (AMR) AF: 0.0824 AC: 3670 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2743 AN: 26062

East Asian (EAS) AF: 0.187 AC: 7378 AN: 39520

South Asian (SAS) AF: 0.0696 AC: 5975 AN: 85882

European-Finnish (FIN) AF: 0.0713 AC: 3802 AN: 53350

Middle Eastern (MID) AF: 0.159 AC: 912 AN: 5746

European-Non Finnish (NFE) AF: 0.0823 AC: 91062 AN: 1106060

Other (OTH) AF: 0.0949 AC: 5703 AN: 60102

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

African (AFR) AF: 0.103 AC: 4263 AN: 41472

American (AMR) AF: 0.0736 AC: 1125 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 352 AN: 3466

East Asian (EAS) AF: 0.196 AC: 1011 AN: 5164

South Asian (SAS) AF: 0.0816 AC: 392 AN: 4806

European-Finnish (FIN) AF: 0.0654 AC: 690 AN: 10558

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.0891 AC: 6057 AN: 67982

Other (OTH) AF: 0.106 AC: 223 AN: 2108

Alfa AF: 0.0922 Hom.: 3117

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
PhyloP100		-0.36
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=96/4	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: rs3794261; hg19: chr12-95906603; COSMIC: COSV51561430; COSMIC: COSV51561430;