Genetic Variant NM_199227.3:c.41G>T (chr2-172061498-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_ModerateBA1

The NM_199227.3(METAP1D):c.41G>T(p.Gly14Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0257 in 1,608,686 control chromosomes in the GnomAD database, including 5,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.030 ( 595 hom., cov: 32)

Exomes 𝑓: 0.025 ( 4747 hom. )

Consequence

METAP1D
NM_199227.3 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.16

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METAP1D	NM_199227.3 link	c.41G>T	p.Gly14Val	missense_variant, splice_region_variant	Exon 2 of 10	ENST00000315796.5	NP_954697.1	Q6UB28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METAP1D	ENST00000315796.5 link	c.41G>T	p.Gly14Val	missense_variant, splice_region_variant	Exon 2 of 10	1	NM_199227.3	ENSP00000315152.4		Q6UB28

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4569

AN:

152024

Hom.:

595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.0723

Gnomad FIN

AF:

0.0559

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00667

Gnomad OTH

AF:

0.0283

GnomAD2 exomes

AF:

0.0560

AC:

13842

AN:

246962

AF XY:

0.0539

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.0327

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.460

Gnomad FIN exome

AF:

0.0529

Gnomad NFE exome

AF:

0.00859

Gnomad OTH exome

AF:

0.0337

GnomAD4 exome

AF:

0.0252

AC:

36697

AN:

1456544

Hom.:

4747

Cov.:

AF XY:

0.0259

AC XY:

18779

AN XY:

724452

show subpopulations

African (AFR)

AF:

0.0115

AC:

380

AN:

33158

American (AMR)

AF:

0.0310

AC:

1359

AN:

43880

Ashkenazi Jewish (ASJ)

AF:

0.00967

AC:

251

AN:

25960

East Asian (EAS)

AF:

0.467

AC:

18438

AN:

39476

South Asian (SAS)

AF:

0.0598

AC:

5082

AN:

85008

European-Finnish (FIN)

AF:

0.0509

AC:

2712

AN:

53304

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00567

AC:

6295

AN:

1109890

Other (OTH)

AF:

0.0350

AC:

2105

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1278

2556

3834

5112

6390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

496

992

1488

1984

2480

<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

AF:

0.0301

AC:

4572

AN:

152142

Hom.:

595

Cov.:

AF XY:

0.0349

AC XY:

2598

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0114

AC:

472

AN:

41508

American (AMR)

AF:

0.0196

AC:

299

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3468

East Asian (EAS)

AF:

0.448

AC:

2313

AN:

5160

South Asian (SAS)

AF:

0.0726

AC:

350

AN:

4822

European-Finnish (FIN)

AF:

0.0559

AC:

591

AN:

10580

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00668

AC:

454

AN:

68010

Other (OTH)

AF:

0.0270

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

168

336

503

671

839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0209

Hom.:

1897

Bravo

AF:

0.0295

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.0554

AC:

6728

Asia WGS

AF:

0.202

AC:

703

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

PhyloP100

7.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

REVEL

Benign

0.16

Sift

Uncertain

0.020

Sift4G

Uncertain

0.026

Polyphen

0.96

Vest4

0.25

MPC

0.18

ClinPred

0.021

GERP RS

6.1

Varity_R

0.27

gMVP

0.36

Mutation Taster

=81/19

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 50

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over