10-27114547-C-T

Variant names:

• chr10-27114547-C-T
• NM_014263.4:c.1981G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014263.4(YME1L1):​c.1981G>A​(p.Glu661Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: YME1L1 NM_014263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YME1L1	NM_014263.4	c.1981G>A	p.Glu661Lys	missense_variant	Exon 18 of 19	ENST00000376016.8	NP_055078.1
YME1L1	NM_139312.3	c.2152G>A	p.Glu718Lys	missense_variant	Exon 19 of 20		NP_647473.1
YME1L1	NM_001253866.2	c.1882G>A	p.Glu628Lys	missense_variant	Exon 17 of 18		NP_001240795.1
YME1L1	XM_011519300.4	c.2053G>A	p.Glu685Lys	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.1981G>A	p.Glu661Lys	missense_variant	Exon 18 of 19	1	NM_014263.4	ENSP00000365184.3
YME1L1	ENST00000326799.7	c.2152G>A	p.Glu718Lys	missense_variant	Exon 19 of 20	1		ENSP00000318480.3
YME1L1	ENST00000613434.4	c.1882G>A	p.Glu628Lys	missense_variant	Exon 17 of 18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461570 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 718 of the YME1L1 protein (p.Glu718Lys). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.0	.;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	.;D;D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	.;D;D;.
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.95, 1.0	.;P;D;.
Vest4		0.90
MutPred		0.76		.;Gain of MoRF binding (P = 0.0046);.;Gain of MoRF binding (P = 0.0046);
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr10-27403476; COSMIC: COSV58759210;