4-99041085-C-A

Variant summary

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

The NM_015143.3(METAP1):​c.475C>A​(p.Pro159Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

METAP1
NM_015143.3 missense

Scores

2
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80
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]

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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
METAP1NM_015143.3 linkc.475C>A p.Pro159Thr missense_variant Exon 6 of 11 ENST00000296411.11 NP_055958.2 P53582

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METAP1ENST00000296411.11 linkc.475C>A p.Pro159Thr missense_variant Exon 6 of 11 1 NM_015143.3 ENSP00000296411.6 P53582

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1456526
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
724442
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.475C>A (p.P159T) alteration is located in exon 6 (coding exon 6) of the METAP1 gene. This alteration results from a C to A substitution at nucleotide position 475, causing the proline (P) at amino acid position 159 to be replaced by a threonine (T). 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
0.13
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.76
D
Eigen
Benign
0.19
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.57
D
MetaSVM
Uncertain
0.070
D
MutationAssessor
Pathogenic
3.5
M
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.54
Sift
Uncertain
0.022
D
Sift4G
Uncertain
0.047
D
Polyphen
0.35
B
Vest4
0.55
MutPred
0.71
Loss of methylation at K158 (P = 0.0963);
MVP
0.84
MPC
0.45
ClinPred
0.91
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-99962236; API