NM_002437.5:c.462-18_*60del

Variant names:

• chr2-27309851-TCTGACCGTTCCAGGGTCAAGCTGCATCACTGCAAGGTGGAAACGATGGAGTGAGGCAGGCTTAGAGCCGATGTGCCTTCCAGGACAGGTAGGAGTTCCAGATAACAGCAACACATTGGACAACGGCCAACCTAAGGAACAGGAATAAC-T
• NM_002437.5:c.462-18_*60del

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_002437.5(MPV17):​c.462-18_*60del variant causes a splice acceptor, splice region, 3 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MPV17 NM_002437.5 splice_acceptor, splice_region, 3_prime_UTR, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.750
• Publications: 0 publications found

Genes affected

MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]

MPV17 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease, axonal, type 2EE

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene.
• PP5: Variant 2-27309851-TCTGACCGTTCCAGGGTCAAGCTGCATCACTGCAAGGTGGAAACGATGGAGTGAGGCAGGCTTAGAGCCGATGTGCCTTCCAGGACAGGTAGGAGTTCCAGATAACAGCAACACATTGGACAACGGCCAACCTAAGGAACAGGAATAAC-T is Pathogenic according to our data. Variant chr2-27309851-TCTGACCGTTCCAGGGTCAAGCTGCATCACTGCAAGGTGGAAACGATGGAGTGAGGCAGGCTTAGAGCCGATGTGCCTTCCAGGACAGGTAGGAGTTCCAGATAACAGCAACACATTGGACAACGGCCAACCTAAGGAACAGGAATAAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2672805.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002437.5. 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
	MPV17	NM_002437.5	MANE Select	c.462-18_*60del	p.Arg154fs	frameshift stop_lost splice_region	Exon 8 of 8	NP_002428.1	P39210
	MPV17	NM_002437.5	MANE Select	c.462-18_*60del		splice_acceptor splice_region 3_prime_UTR intron	Exon 8 of 8	NP_002428.1	P39210

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPV17	ENST00000380044.6	TSL:1 MANE Select	c.462-18_*60del	p.Arg154fs	frameshift stop_lost splice_region	Exon 8 of 8	ENSP00000369383.1	P39210
	MPV17	ENST00000233545.6	TSL:1	c.462-18_*60del	p.Arg154fs	frameshift stop_lost splice_region	Exon 7 of 7	ENSP00000233545.2	P39210
	MPV17	ENST00000380044.6	TSL:1 MANE Select	c.462-18_*60del		splice_acceptor splice_region 3_prime_UTR intron	Exon 8 of 8	ENSP00000369383.1	P39210

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-27532719;