Genetic Variant METAP1D:p.Arg105Gly (chr2-172063825-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_199227.3(METAP1D):c.313C>G(p.Arg105Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R105C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

METAP1D
NM_199227.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.68

Publications

1 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.765

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199227.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METAP1D	NM_199227.3	MANE Select	c.313C>G	p.Arg105Gly	missense	Exon 3 of 10	NP_954697.1	Q6UB28
METAP1D	NM_001322278.2		c.-128C>G		5_prime_UTR	Exon 3 of 10	NP_001309207.1
METAP1D	NM_001322279.2		c.-42C>G		5_prime_UTR	Exon 3 of 10	NP_001309208.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METAP1D	ENST00000315796.5	TSL:1 MANE Select	c.313C>G	p.Arg105Gly	missense	Exon 3 of 10	ENSP00000315152.4	Q6UB28
METAP1D	ENST00000913778.1		c.415C>G	p.Arg139Gly	missense	Exon 4 of 11	ENSP00000583837.1
METAP1D	ENST00000913779.1		c.373C>G	p.Arg125Gly	missense	Exon 4 of 11	ENSP00000583838.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250734

AF XY:

0.0000148

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461378

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111784

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

-0.021

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.5

PhyloP100

2.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.56

Sift

Benign

0.26

Sift4G

Benign

0.34

Polyphen

0.052

Vest4

0.73

MutPred

0.68

Loss of stability (P = 0.026)

MVP

0.77

MPC

0.67

ClinPred

0.92

GERP RS

4.8

Varity_R

0.53

gMVP

0.90

Mutation Taster

=51/49

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over