Genetic Variant NM_006838.4:c.824C>A (chr12-95496055-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006838.4(METAP2):c.824C>A(p.Thr275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T275M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

METAP2
NM_006838.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.332

Publications

2 publications found

Variant links:

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]

METAP2 links:

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ACMG classification

Classification was made for transcript

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 (MetaRNN=0.03514284).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006838.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METAP2	NM_006838.4	MANE Select	c.824C>A	p.Thr275Lys	missense	Exon 7 of 11	NP_006829.1	A0A140VJE3
METAP2	NM_001330246.2		c.821C>A	p.Thr274Lys	missense	Exon 7 of 11	NP_001317175.1	F8VQZ7
METAP2	NM_001317182.2		c.755C>A	p.Thr252Lys	missense	Exon 7 of 11	NP_001304111.1	P50579-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METAP2	ENST00000323666.10	TSL:1 MANE Select	c.824C>A	p.Thr275Lys	missense	Exon 7 of 11	ENSP00000325312.5	P50579-1
METAP2	ENST00000878867.1		c.842C>A	p.Thr281Lys	missense	Exon 7 of 11	ENSP00000548926.1
METAP2	ENST00000551840.5	TSL:5	c.821C>A	p.Thr274Lys	missense	Exon 7 of 11	ENSP00000450063.1	F8VQZ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248436

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33150

American (AMR)

AF:

0.00

AC:

AN:

44448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26040

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39442

South Asian (SAS)

AF:

0.00

AC:

AN:

85512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101230

Other (OTH)

AF:

0.00

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.1

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.18

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.020

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

PhyloP100

0.33

PrimateAI

Benign

0.33

PROVEAN

Benign

1.6

REVEL

Benign

0.12

Sift

Benign

0.72

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.21

MutPred

0.33

Gain of methylation at T275 (P = 0.0581)

MVP

0.19

MPC

0.67

ClinPred

0.029

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.086

gMVP

0.54

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over