Variant rs267607264 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_002437.5(MPV17):c.271_273del(p.Leu91del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000112 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MPV17
NM_002437.5 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 5.11

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a chain Protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002437.5

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_002437.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 2-27312685-CCAA-C is Pathogenic according to our data. Variant chr2-27312685-CCAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MPV17	NM_002437.5 linkuse as main transcript	c.271_273del	p.Leu91del	inframe_deletion	4/8	ENST00000380044.6	NP_002428.1
MPV17	XM_005264326.5 linkuse as main transcript	c.271_273del	p.Leu91del	inframe_deletion	4/8		XP_005264383.1
MPV17	XM_017004151.2 linkuse as main transcript	c.223_225del	p.Leu75del	inframe_deletion	4/8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6 linkuse as main transcript	c.271_273del	p.Leu91del	inframe_deletion	4/8	1	NM_002437.5	ENSP00000369383	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251476

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461854

Hom.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This variant, c.271_273del, results in the deletion of 1 amino acid(s) of the MPV17 protein (p.Leu91del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs267607264, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 20074988, 29282788, 32703289, 33258288; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38353). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2016	- -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 11, 2021

Variant summary: MPV17 c.271_273delTTG (p.Leu91del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251476 control chromosomes. c.271_273delTTG has been reported in the literature in individuals affected with MPV17 related Mitochondrial DNA Depletion Syndrome (example, El-Hattab_2010, El-Hattab_2018, Quaio_2020, Shimura_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance citing a classification dated earlier than the most recent evidence in the literature cited above. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Charcot-Marie-Tooth disease, axonal, type 2EE

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over