2-172061498-G-T

Variant names:

• chr2-172061498-G-T
• rs10497377
• NM_199227.3:c.41G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

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

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]

ACMG classification

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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METAP1D	NM_199227.3	MANE Select	c.41G>T	p.Gly14Val	missense splice_region	Exon 2 of 10	NP_954697.1
	METAP1D	NM_001322278.2		c.-400G>T		splice_region	Exon 2 of 10	NP_001309207.1
	METAP1D	NM_001322279.2		c.-314G>T		splice_region	Exon 2 of 10	NP_001309208.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METAP1D	ENST00000315796.5	TSL:1 MANE Select	c.41G>T	p.Gly14Val	missense splice_region	Exon 2 of 10	ENSP00000315152.4
	METAP1D	ENST00000491440.1	TSL:3	n.70G>T		splice_region non_coding_transcript_exon	Exon 2 of 3
	METAP1D	ENST00000493035.5	TSL:2	n.68G>T		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4569 AN: 152024 Hom.: 595 Cov.: 32

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

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.: 31 AF XY: 0.0259 AC XY: 18779 AN XY: 724452

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: 75 AN: 5726

European-Non Finnish (NFE) AF: 0.00567 AC: 6295 AN: 1109890

Other (OTH) AF: 0.0350 AC: 2105 AN: 60142

GnomAD4 genome AF: 0.0301 AC: 4572 AN: 152142 Hom.: 595 Cov.: 32 AF XY: 0.0349 AC XY: 2598 AN XY: 74374

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: 30 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: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00668 AC: 454 AN: 68010

Other (OTH) AF: 0.0270 AC: 57 AN: 2108

Alfa AF: 0.0209 Hom.: 1897

Bravo AF: 0.0295

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.0554 AC: 6728

Asia WGS AF: 0.202 AC: 703 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.026	D
Polyphen		0.96	D
Vest4		0.25
MPC		0.18
ClinPred		0.021	T
GERP RS		6.1
Varity_R		0.27
gMVP		0.36
Mutation Taster		=81/19	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10497377; hg19: chr2-172926226; COSMIC: COSV59929316; COSMIC: COSV59929316;