chr2-189755405-A-G

Variant names:

• chr2-189755405-A-G
• NM_022353.3:c.377T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022353.3(OSGEPL1):​c.377T>C​(p.Val126Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,114 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V126M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OSGEPL1 NM_022353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022353.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSGEPL1	NM_022353.3	MANE Select	c.377T>C	p.Val126Ala	missense	Exon 3 of 9	NP_071748.2	Q9H4B0-1
	OSGEPL1	NM_001354347.2		c.377T>C	p.Val126Ala	missense	Exon 3 of 9	NP_001341276.2	Q9H4B0-1
	OSGEPL1	NM_001376077.1		c.377T>C	p.Val126Ala	missense	Exon 3 of 9	NP_001363006.1	Q9H4B0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSGEPL1	ENST00000264151.10	TSL:1 MANE Select	c.377T>C	p.Val126Ala	missense	Exon 3 of 9	ENSP00000264151.5	Q9H4B0-1
	OSGEPL1	ENST00000522700.5	TSL:1	c.377T>C	p.Val126Ala	missense	Exon 3 of 8	ENSP00000429697.1	Q9H4B0-1
	OSGEPL1	ENST00000868797.1		c.377T>C	p.Val126Ala	missense	Exon 3 of 9	ENSP00000538856.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459114 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725824

African (AFR) AF: 0.00 AC: 0 AN: 33252

American (AMR) AF: 0.00 AC: 0 AN: 43752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111280

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.36
Sift	Benign	0.050	D
Sift4G	Uncertain	0.058	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.81		Loss of stability (P = 0.0469)
MVP		0.64
MPC		0.66
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.35
gMVP		0.83
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-190620131;