chr2-172000006-A-G

Variant names:

• chr2-172000006-A-G
• rs891514720
• NM_199227.3:c.37A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199227.3(METAP1D):​c.37A>G​(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,339,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: METAP1D NM_199227.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.350
• 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]

SLC25A12 (HGNC:10982): (solute carrier family 25 member 12) This gene encodes a calcium-binding mitochondrial carrier protein. The encoded protein localizes to the mitochondria and is involved in the exchange of aspartate for glutamate across the inner mitochondrial membrane. Polymorphisms in this gene may be associated with autism, and mutations in this gene may also be a cause of global cerebral hypomyelination. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

SLC25A12 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 39

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

LOC124905590 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080289036).

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.37A>G	p.Arg13Gly	missense	Exon 1 of 10	NP_954697.1	Q6UB28
	METAP1D	NM_001322278.2		c.-404A>G		5_prime_UTR	Exon 1 of 10	NP_001309207.1
	METAP1D	NM_001322279.2		c.-368A>G		5_prime_UTR	Exon 1 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.37A>G	p.Arg13Gly	missense	Exon 1 of 10	ENSP00000315152.4	Q6UB28
	METAP1D	ENST00000913778.1		c.37A>G	p.Arg13Gly	missense	Exon 1 of 11	ENSP00000583837.1
	METAP1D	ENST00000913779.1		c.37A>G	p.Arg13Gly	missense	Exon 1 of 11	ENSP00000583838.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000421 AC: 5 AN: 1187288 Hom.: 0 Cov.: 33 AF XY: 0.00000523 AC XY: 3 AN XY: 574000

African (AFR) AF: 0.0000422 AC: 1 AN: 23714

American (AMR) AF: 0.00 AC: 0 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16320

East Asian (EAS) AF: 0.00 AC: 0 AN: 27038

South Asian (SAS) AF: 0.00 AC: 0 AN: 47474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4542

European-Non Finnish (NFE) AF: 0.00000413 AC: 4 AN: 968546

Other (OTH) AF: 0.00 AC: 0 AN: 47364

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152254 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41480

American (AMR) AF: 0.000262 AC: 4 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	Benign	0.070
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.6
DANN	Benign	0.57
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.35
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.066
Sift	Benign	0.45	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.42		Loss of MoRF binding (P = 0.0071)
MVP		0.19
MPC		0.18
ClinPred		0.12	T
GERP RS		-3.2
PromoterAI		-0.075	Neutral
Varity_R		0.074
gMVP		0.35
Mutation Taster		=95/5	polymorphism

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: rs891514720; hg19: chr2-172864913;