2-172077836-T-A

Position:

• chr2-172077836-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000315796.5(METAP1D):​c.744T>A​(p.His248Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: METAP1D ENST00000315796.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.250

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24327895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METAP1D	NM_199227.3	c.744T>A	p.His248Gln	missense_variant	7/10	ENST00000315796.5	NP_954697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METAP1D	ENST00000315796.5	c.744T>A	p.His248Gln	missense_variant	7/10	1	NM_199227.3	ENSP00000315152	P1
METAP1D	ENST00000468537.1	n.448T>A		non_coding_transcript_exon_variant	2/4	2
METAP1D	ENST00000488581.5	n.480T>A		non_coding_transcript_exon_variant	5/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.744T>A (p.H248Q) alteration is located in exon 7 (coding exon 7) of the METAP1D gene. This alteration results from a T to A substitution at nucleotide position 744, causing the histidine (H) at amino acid position 248 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	0.76	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.24
Sift	Benign	0.30	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.46
MutPred		0.78		Loss of sheet (P = 0.1158);
MVP		0.54
MPC		0.17
ClinPred		0.29	T
GERP RS		0.69
Varity_R		0.13
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-172942564;