2-172065668-A-G

Variant names:

• chr2-172065668-A-G
• rs900546688
• NM_199227.3:c.413A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_199227.3(METAP1D):​c.413A>G​(p.Tyr138Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: METAP1D NM_199227.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.69
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METAP1D	NM_199227.3	MANE Select	c.413A>G	p.Tyr138Cys	missense	Exon 4 of 10	NP_954697.1	Q6UB28
	METAP1D	NM_001322278.2		c.59A>G	p.Tyr20Cys	missense	Exon 4 of 10	NP_001309207.1
	METAP1D	NM_001322279.2		c.59A>G	p.Tyr20Cys	missense	Exon 4 of 10	NP_001309208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METAP1D	ENST00000315796.5	TSL:1 MANE Select	c.413A>G	p.Tyr138Cys	missense	Exon 4 of 10	ENSP00000315152.4	Q6UB28
	METAP1D	ENST00000913778.1		c.515A>G	p.Tyr172Cys	missense	Exon 5 of 11	ENSP00000583837.1
	METAP1D	ENST00000913779.1		c.473A>G	p.Tyr158Cys	missense	Exon 5 of 11	ENSP00000583838.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251334 AF XY: 0.00000736

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: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461692 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111904

Other (OTH) AF: 0.0000331 AC: 2 AN: 60378

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		8.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.55		Gain of catalytic residue at S140 (P = 0.0581)
MVP		0.74
MPC		0.70
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs900546688; hg19: chr2-172930396;