10-27114529-G-C

Variant names:

• chr10-27114529-G-C
• NM_014263.4:c.1999C>G

Variant summary

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

The NM_014263.4(YME1L1):​c.1999C>G​(p.Leu667Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: YME1L1 NM_014263.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.86

Genes affected

YME1L1 (HGNC:12843): (YME1 like 1 ATPase) The protein encoded by this gene is the human ortholog of yeast mitochondrial AAA metalloprotease, Yme1p. It is localized in the mitochondria and can functionally complement a yme1 disruptant yeast strain. It is proposed that this gene plays a role in mitochondrial protein metabolism and could be involved in mitochondrial pathologies. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YME1L1	NM_014263.4	c.1999C>G	p.Leu667Val	missense_variant	Exon 18 of 19	ENST00000376016.8	NP_055078.1
YME1L1	NM_139312.3	c.2170C>G	p.Leu724Val	missense_variant	Exon 19 of 20		NP_647473.1
YME1L1	NM_001253866.2	c.1900C>G	p.Leu634Val	missense_variant	Exon 17 of 18		NP_001240795.1
YME1L1	XM_011519300.4	c.2071C>G	p.Leu691Val	missense_variant	Exon 18 of 19		XP_011517602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YME1L1	ENST00000376016.8	c.1999C>G	p.Leu667Val	missense_variant	Exon 18 of 19	1	NM_014263.4	ENSP00000365184.3
YME1L1	ENST00000326799.7	c.2170C>G	p.Leu724Val	missense_variant	Exon 19 of 20	1		ENSP00000318480.3
YME1L1	ENST00000613434.4	c.1900C>G	p.Leu634Val	missense_variant	Exon 17 of 18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Methylglutaconic aciduria Pathogenic:1

Sep 02, 2024

Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

The NM_014263.4(YME1L1):c.1999C>G p.(Leu667Val) is a missense variant that replaces the highly conserved leucine at position 667 to valine within the C-terminal metalloprotease domain of the protein. This variant is absent from the gnomAD and other population databases (PM2_Moderate). The aggregated score (0.726) of in silico prediction tools, predicts a deleterious effect (PP3_Supporting). YME1L1 is an ATP-dependent metalloprotease embedded in the inner mitochondrial membrane and has an important role in regulating mitochondrial homeostasis and morphology. It is implicated in the processing of OPA1, a crucial mediator of mitochondrial fusion and in degradation of other mitochondrial proteins, such as lipid transfer proteins and components of protein translocases. Our in vitro functional studies on patient-derived fibroblasts provide evidence that the c.1999C>G p.(Leu667Val) variant results in impaired YME1L1 proteolytic activity, as revealed by the accumulation of PRELID1 and abnormal OPA1 processing as compared to control fibroblasts. Moreover, mitochondrial fragmentation was observed in patients’ fibroblasts (PS3_strong). This variant co-segregates with the disease (PP1_supporting). In summary, this variant meets the criteria to be classified as likely pathogenic, according to the recommendations of The American College of Medical Genetics and Genomics (ACMG). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.1	.;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	.;N;N;.
REVEL	Pathogenic	0.74
Sift	Benign	0.071	.;T;T;.
Sift4G	Uncertain	0.048	D;T;T;T
Polyphen		0.99, 0.99	.;D;D;.
Vest4		0.68
MutPred		0.70		.;Loss of catalytic residue at L724 (P = 0.0084);.;Loss of catalytic residue at L724 (P = 0.0084);
MVP		0.39
MPC		1.9
ClinPred		0.77	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr10-27403458;