dbSNP rs10497377: METAP1D:p.Gly14Asp (chr2-172061498-G-A) – 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.41G>A(p.Gly14Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000275 in 1,456,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

METAP1D
NM_199227.3 missense, splice_region

Scores

Splicing: ADA: 0.9988

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:

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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

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

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
METAP1D	NM_199227.3	MANE Select	c.41G>A	p.Gly14Asp	missense splice_region	Exon 2 of 10	NP_954697.1
METAP1D	NM_001322278.2		c.-400G>A		splice_region	Exon 2 of 10	NP_001309207.1
METAP1D	NM_001322279.2		c.-314G>A		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>A	p.Gly14Asp	missense splice_region	Exon 2 of 10	ENSP00000315152.4
METAP1D	ENST00000491440.1	TSL:3	n.70G>A		splice_region non_coding_transcript_exon	Exon 2 of 3
METAP1D	ENST00000493035.5	TSL:2	n.68G>A		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000810

AC:

AN:

246962

AF XY:

0.00000749

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000598

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000275

AC:

AN:

1456648

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724522

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.0000228

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:

0.00000270

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

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:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.56

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.1

PhyloP100

7.2

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.7

REVEL

Benign

0.21

Sift

Uncertain

0.014

Sift4G

Uncertain

0.035

Polyphen

0.98

Vest4

0.50

MutPred

0.47

Loss of MoRF binding (P = 0.0218)

MVP

0.61

MPC

0.19

ClinPred

0.63

GERP RS

6.1

Varity_R

0.23

gMVP

0.51

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.050

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over