chr2-172000006-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_199227.3(METAP1D):​c.37A>C​(p.Arg13Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,339,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: METAP1D NM_199227.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP7: Synonymous conserved (PhyloP=-0.35 with no splicing effect.

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>C	p.Arg13Arg	synonymous	Exon 1 of 10	NP_954697.1	Q6UB28
	METAP1D	NM_001322278.2		c.-404A>C		5_prime_UTR	Exon 1 of 10	NP_001309207.1
	METAP1D	NM_001322279.2		c.-368A>C		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>C	p.Arg13Arg	synonymous	Exon 1 of 10	ENSP00000315152.4	Q6UB28
	METAP1D	ENST00000913778.1		c.37A>C	p.Arg13Arg	synonymous	Exon 1 of 11	ENSP00000583837.1
	METAP1D	ENST00000913779.1		c.37A>C	p.Arg13Arg	synonymous	Exon 1 of 11	ENSP00000583838.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000337 AC: 4 AN: 1187288 Hom.: 0 Cov.: 33 AF XY: 0.00000348 AC XY: 2 AN XY: 574000

African (AFR) AF: 0.00 AC: 0 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: 0.0000239 AC: 1 AN: 41794

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

European-Non Finnish (NFE) AF: 0.00000310 AC: 3 AN: 968546

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.0000241 AC: 1 AN: 41480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	6.0
DANN	Benign	0.44
PhyloP100		-0.35
PromoterAI		-0.0065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	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;