2-189755286-A-T

Position:

• chr2-189755286-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022353.3(OSGEPL1):​c.496T>A​(p.Leu166Ile) variant causes a missense change involving the alteration of a non-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: 33)
• Consequence: OSGEPL1 NM_022353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

Genes affected

OSGEPL1 (HGNC:23075): (O-sialoglycoprotein endopeptidase like 1) Predicted to enable N(6)-L-threonylcarbamoyladenine synthase activity and metal ion binding activity. Predicted to be involved in tRNA threonylcarbamoyladenosine modification. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ANKAR (HGNC:26350): (ankyrin and armadillo repeat containing) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSGEPL1	NM_022353.3	c.496T>A	p.Leu166Ile	missense_variant	3/9	ENST00000264151.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSGEPL1	ENST00000264151.10	c.496T>A	p.Leu166Ile	missense_variant	3/9	1	NM_022353.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.496T>A (p.L166I) alteration is located in exon 3 (coding exon 2) of the OSGEPL1 gene. This alteration results from a T to A substitution at nucleotide position 496, causing the leucine (L) at amino acid position 166 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T;.;T;.;T;T
Eigen	Benign	0.071
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.9	L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0080	D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;.;D
Polyphen		0.72	P;.;P;.;.;.
Vest4		0.67
MutPred		0.57		Loss of catalytic residue at L166 (P = 0.0444);Loss of catalytic residue at L166 (P = 0.0444);Loss of catalytic residue at L166 (P = 0.0444);.;Loss of catalytic residue at L166 (P = 0.0444);Loss of catalytic residue at L166 (P = 0.0444);
MVP		0.67
MPC		0.57
ClinPred		0.87	D
GERP RS		2.0
Varity_R		0.47
gMVP		0.66

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: rs1210501406; hg19: chr2-190620012;