4-99039397-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015143.3(METAP1):​c.364C>T​(p.Leu122Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

METAP1
NM_015143.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.1311135).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METAP1NM_015143.3 linkc.364C>T p.Leu122Phe missense_variant Exon 5 of 11 ENST00000296411.11 NP_055958.2 P53582

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METAP1ENST00000296411.11 linkc.364C>T p.Leu122Phe missense_variant Exon 5 of 11 1 NM_015143.3 ENSP00000296411.6 P53582

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1458542
Hom.:
0
Cov.:
28
AF XY:
0.00000689
AC XY:
5
AN XY:
725642
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:
0.00000631
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152000
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74218
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.364C>T (p.L122F) alteration is located in exon 5 (coding exon 5) of the METAP1 gene. This alteration results from a C to T substitution at nucleotide position 364, causing the leucine (L) at amino acid position 122 to be replaced by a phenylalanine (F). 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
Benign
0.25
BayesDel_addAF
Benign
-0.029
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Benign
0.92
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.080
Eigen_PC
Benign
0.087
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.4
L
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.095
Sift
Benign
0.72
T
Sift4G
Benign
0.73
T
Polyphen
0.0
B
Vest4
0.38
MutPred
0.28
Gain of methylation at K123 (P = 0.0298);
MVP
0.65
MPC
0.43
ClinPred
0.38
T
GERP RS
4.9
Varity_R
0.16
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs763770814; hg19: chr4-99960548; API