10-27111990-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014263.4(YME1L1):c.2138T>C(p.Leu713Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YME1L1 NM_014263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, YME1L1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YME1L1	NM_014263.4	c.2138T>C	p.Leu713Ser	missense_variant	19/19	ENST00000376016.8
YME1L1	NM_139312.3	c.2309T>C	p.Leu770Ser	missense_variant	20/20
YME1L1	NM_001253866.2	c.2039T>C	p.Leu680Ser	missense_variant	18/18
YME1L1	XM_011519300.4	c.2210T>C	p.Leu737Ser	missense_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YME1L1	ENST00000376016.8	c.2138T>C	p.Leu713Ser	missense_variant	19/19	1	NM_014263.4	P1
YME1L1	ENST00000326799.7	c.2309T>C	p.Leu770Ser	missense_variant	20/20	1
YME1L1	ENST00000613434.4	c.2039T>C	p.Leu680Ser	missense_variant	18/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with YME1L1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 770 of the YME1L1 protein (p.Leu770Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.0039	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.65
MutPred		0.38		.;Gain of phosphorylation at L770 (P = 0.0252);.;
MVP		0.51
MPC		2.2
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.40
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-27400919;