10-27112099-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_014263.4(YME1L1):c.2029C>T(p.His677Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H677R) has been classified 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: 2.43

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.

• PM1: In a binding_site (size 0) in uniprot entity YMEL1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, YME1L1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15230507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YME1L1	NM_014263.4	c.2029C>T	p.His677Tyr	missense_variant	19/19	ENST00000376016.8
YME1L1	NM_139312.3	c.2200C>T	p.His734Tyr	missense_variant	20/20
YME1L1	NM_001253866.2	c.1930C>T	p.His644Tyr	missense_variant	18/18
YME1L1	XM_011519300.4	c.2101C>T	p.His701Tyr	missense_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YME1L1	ENST00000376016.8	c.2029C>T	p.His677Tyr	missense_variant	19/19	1	NM_014263.4	P1
YME1L1	ENST00000326799.7	c.2200C>T	p.His734Tyr	missense_variant	20/20	1
YME1L1	ENST00000613434.4	c.1930C>T	p.His644Tyr	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

Dec 15, 2021

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 734 of the YME1L1 protein (p.His734Tyr). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.10
BayesDel_addAF	Benign	0.0072	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	0.86	D;N;N
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.59, 0.0080	.;P;B;.
Vest4		0.32
MutPred		0.42		.;Loss of disorder (P = 0.042);.;Loss of disorder (P = 0.042);
MVP		0.23
MPC		1.3
ClinPred		0.40	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.094
gMVP		0.46

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: chr10-27401028;