chr10-27114576-T-C

Position:

• chr10-27114576-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000376016.8(YME1L1):​c.1952A>G​(p.Lys651Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YME1L1 ENST00000376016.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), YME1L1. . Gene score misZ 2.5125 (greater than the threshold 3.09). Trascript score misZ 3.2015 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive optic atrophy, optic atrophy 11.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21407619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YME1L1	NM_014263.4	c.1952A>G	p.Lys651Arg	missense_variant	18/19	ENST00000376016.8	NP_055078.1
YME1L1	NM_139312.3	c.2123A>G	p.Lys708Arg	missense_variant	19/20		NP_647473.1
YME1L1	NM_001253866.2	c.1853A>G	p.Lys618Arg	missense_variant	17/18		NP_001240795.1
YME1L1	XM_011519300.4	c.2024A>G	p.Lys675Arg	missense_variant	18/19		XP_011517602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YME1L1	ENST00000376016.8	c.1952A>G	p.Lys651Arg	missense_variant	18/19	1	NM_014263.4	ENSP00000365184	P1
YME1L1	ENST00000326799.7	c.2123A>G	p.Lys708Arg	missense_variant	19/20	1		ENSP00000318480
YME1L1	ENST00000613434.4	c.1853A>G	p.Lys618Arg	missense_variant	17/18	2		ENSP00000481724

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2022

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 708 of the YME1L1 protein (p.Lys708Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with YME1L1-related conditions. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;T
Eigen	Benign	0.075
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	0.72	.;N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	.;N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.18	.;T;T;.
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.17, 0.0070	.;B;B;.
Vest4		0.22
MutPred		0.36		.;Loss of ubiquitination at K708 (P = 0.0063);.;Loss of ubiquitination at K708 (P = 0.0063);
MVP		0.52
MPC		1.4
ClinPred		0.82	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.42

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

Other links and lift over

dbSNP: rs894467464; hg19: chr10-27403505;