2-189755207-G-A

Variant names:

• chr2-189755207-G-A
• rs1472939869
• NM_022353.3:c.575C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022353.3(OSGEPL1):​c.575C>T​(p.Ser192Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S192C) 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: Not reported in ClinVar
• Conservation: PhyloP100: 6.67
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

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.575C>T	p.Ser192Phe	missense	Exon 3 of 9	NP_071748.2	Q9H4B0-1
	OSGEPL1	NM_001354347.2		c.575C>T	p.Ser192Phe	missense	Exon 3 of 9	NP_001341276.2	Q9H4B0-1
	OSGEPL1	NM_001376077.1		c.575C>T	p.Ser192Phe	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.575C>T	p.Ser192Phe	missense	Exon 3 of 9	ENSP00000264151.5	Q9H4B0-1
	OSGEPL1	ENST00000522700.5	TSL:1	c.575C>T	p.Ser192Phe	missense	Exon 3 of 8	ENSP00000429697.1	Q9H4B0-1
	OSGEPL1	ENST00000868797.1		c.575C>T	p.Ser192Phe	missense	Exon 3 of 9	ENSP00000538856.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459446 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726020

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111340

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.93	P
Vest4		0.50
MutPred		0.84		Loss of ubiquitination at K191 (P = 0.1151)
MVP		0.83
MPC		0.62
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.84
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs1472939869; hg19: chr2-190619933;