10-27112098-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Strong

The NM_014263.4(YME1L1):c.2030A>G(p.His677Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. H677Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: YME1L1 NM_014263.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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.

• 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=0.06675786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YME1L1	NM_014263.4	c.2030A>G	p.His677Arg	missense_variant	19/19	ENST00000376016.8
YME1L1	NM_139312.3	c.2201A>G	p.His734Arg	missense_variant	20/20
YME1L1	NM_001253866.2	c.1931A>G	p.His644Arg	missense_variant	18/18
YME1L1	XM_011519300.4	c.2102A>G	p.His701Arg	missense_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YME1L1	ENST00000376016.8	c.2030A>G	p.His677Arg	missense_variant	19/19	1	NM_014263.4	P1
YME1L1	ENST00000326799.7	c.2201A>G	p.His734Arg	missense_variant	20/20	1
YME1L1	ENST00000613434.4	c.1931A>G	p.His644Arg	missense_variant	18/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250918 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461470 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Feb 16, 2023

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 tolerated. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 734 of the YME1L1 protein (p.His734Arg). This variant is present in population databases (rs142481948, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with YME1L1-related conditions. 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	-0.067	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Benign	0.83
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	0.93	D;N;N
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.021, 0.0	.;B;B;.
Vest4		0.28
MutPred		0.34		.;Gain of MoRF binding (P = 0.0183);.;Gain of MoRF binding (P = 0.0183);
MVP		0.41
MPC		1.0
ClinPred		0.036	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
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: rs142481948; hg19: chr10-27401027;