Genetic Variant METAP1:p.Thr24Ser (chr4-98995824-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_015143.3(METAP1):c.71C>G(p.Thr24Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000216 in 1,391,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

METAP1
NM_015143.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

METAP1 (HGNC:15789): (methionyl aminopeptidase 1) Predicted to enable aminopeptidase activity and metalloexopeptidase activity. Involved in platelet aggregation. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

METAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METAP1	NM_015143.3 link	c.71C>G	p.Thr24Ser	missense_variant	Exon 1 of 11	ENST00000296411.11	NP_055958.2	P53582
METAP1	XM_011531779.3 link	c.71C>G	p.Thr24Ser	missense_variant	Exon 1 of 10		XP_011530081.1
METAP1	XM_017007914.3 link	c.71C>G	p.Thr24Ser	missense_variant	Exon 1 of 10		XP_016863403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METAP1	ENST00000296411.11 link	c.71C>G	p.Thr24Ser	missense_variant	Exon 1 of 11	1	NM_015143.3	ENSP00000296411.6		P53582

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000682

AC:

AN:

146528

Hom.:

AF XY:

0.00

AC XY:

AN XY:

78298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1391978

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71C>G (p.T24S) alteration is located in exon 1 (coding exon 1) of the METAP1 gene. This alteration results from a C to G substitution at nucleotide position 71, causing the threonine (T) at amino acid position 24 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.011

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.1

N;.

REVEL

Uncertain

0.39

Sift

Benign

0.066

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.0050

B;.

Vest4

0.41

MutPred

0.34

Gain of disorder (P = 0.0541);Gain of disorder (P = 0.0541);

MVP

0.59

MPC

0.35

ClinPred

0.55

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over