2-172063828-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_199227.3(METAP1D):​c.316C>T​(p.His106Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

METAP1D
NM_199227.3 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.17
Variant links:
Genes affected
METAP1D (HGNC:32583): (methionyl aminopeptidase type 1D, mitochondrial) The N-terminal methionine excision pathway is an essential process in which the N-terminal methionine is removed from many proteins, thus facilitating subsequent protein modification. In mitochondria, enzymes that catalyze this reaction are celled methionine aminopeptidases (MetAps, or MAPs; EC 3.4.11.18) (Serero et al., 2003 [PubMed 14532271]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38415062).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METAP1DNM_199227.3 linkc.316C>T p.His106Tyr missense_variant Exon 3 of 10 ENST00000315796.5 NP_954697.1 Q6UB28

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METAP1DENST00000315796.5 linkc.316C>T p.His106Tyr missense_variant Exon 3 of 10 1 NM_199227.3 ENSP00000315152.4 Q6UB28
METAP1DENST00000488581.5 linkn.201C>T non_coding_transcript_exon_variant Exon 2 of 7 3
METAP1DENST00000493035.5 linkn.343C>T non_coding_transcript_exon_variant Exon 3 of 3 2
METAP1DENST00000491440.1 linkn.*78C>T downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250784
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135538
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000546
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461392
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726972
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000793

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 24, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.316C>T (p.H106Y) alteration is located in exon 3 (coding exon 3) of the METAP1D gene. This alteration results from a C to T substitution at nucleotide position 316, causing the histidine (H) at amino acid position 106 to be replaced by a tyrosine (Y). 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
0.10
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.35
T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.38
T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
1.2
L
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.44
Sift
Benign
0.11
T
Sift4G
Benign
0.15
T
Polyphen
0.057
B
Vest4
0.58
MutPred
0.52
Loss of catalytic residue at L108 (P = 0.1309);
MVP
0.66
MPC
0.56
ClinPred
0.78
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.46
gMVP
0.76

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.

Other links and lift over

dbSNP: rs912021089; hg19: chr2-172928556; API