8-98949209-C-A

Position:

• chr8-98949209-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001142462.3(OSR2):​c.257C>A​(p.Pro86Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OSR2 NM_001142462.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

Genes affected

OSR2 (HGNC:15830): (odd-skipped related transciption factor 2) OSR2 is a mammalian homolog of the Drosophila odd-skipped family of transcription factors (Lan et al., 2004 [PubMed 15175245]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.375328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSR2	NM_001142462.3	c.257C>A	p.Pro86Gln	missense_variant	2/4	ENST00000297565.9	NP_001135934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSR2	ENST00000297565.9	c.257C>A	p.Pro86Gln	missense_variant	2/4	1	NM_001142462.3	ENSP00000297565.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439358 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 713116

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 31, 2022

The c.257C>A (p.P86Q) alteration is located in exon 2 (coding exon 1) of the OSR2 gene. This alteration results from a C to A substitution at nucleotide position 257, causing the proline (P) at amino acid position 86 to be replaced by a glutamine (Q). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	.;T;T;.;T;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;.;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;L;L;L;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N;D;N;N;N;N;D
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		0.99, 0.97, 0.99	.;D;D;D;D;.;.
Vest4		0.48
MutPred		0.41		.;Gain of catalytic residue at P86 (P = 0.064);Gain of catalytic residue at P86 (P = 0.064);Gain of catalytic residue at P86 (P = 0.064);Gain of catalytic residue at P86 (P = 0.064);.;Gain of catalytic residue at P86 (P = 0.064);
MVP		0.41
MPC		0.74
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.19
gMVP		0.77

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: rs201438766; hg19: chr8-99961437;