Genetic Variant METAP1D:p.Gly14Ala (chr2-172061498-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000315796.5(METAP1D):c.41G>C(p.Gly14Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,456,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G14V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

METAP1D
ENST00000315796.5 missense, splice_region

Scores

Splicing: ADA: 0.8526

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.16

Publications

0 publications found

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]

METAP1D links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000315796.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
METAP1D	NM_199227.3	MANE Select	c.41G>C	p.Gly14Ala	missense splice_region	Exon 2 of 10	NP_954697.1
METAP1D	NM_001322278.2		c.-400G>C		splice_region	Exon 2 of 10	NP_001309207.1
METAP1D	NM_001322279.2		c.-314G>C		splice_region	Exon 2 of 10	NP_001309208.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
METAP1D	ENST00000315796.5	TSL:1 MANE Select	c.41G>C	p.Gly14Ala	missense splice_region	Exon 2 of 10	ENSP00000315152.4
METAP1D	ENST00000491440.1	TSL:3	n.70G>C		splice_region non_coding_transcript_exon	Exon 2 of 3
METAP1D	ENST00000493035.5	TSL:2	n.68G>C		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456648

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724522

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.00

AC:

AN:

43880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00

AC:

AN:

85036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109914

Other (OTH)

AF:

0.00

AC:

AN:

60152

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

0.0082

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.011

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.56

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

7.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

REVEL

Benign

0.21

Sift

Benign

0.13

Sift4G

Benign

0.16

Polyphen

0.096

Vest4

0.49

MutPred

0.38

Loss of sheet (P = 0.0457)

MVP

0.43

MPC

0.16

ClinPred

0.85

GERP RS

6.1

Varity_R

0.14

gMVP

0.39

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Benign

0.67

SpliceAI score (max)

0.090

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over