Genetic Variant NM_145260.3:c.752C>T (chr2-19352324-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_145260.3(OSR1):c.752C>T(p.Thr251Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

OSR1
NM_145260.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.78

Publications

0 publications found

Variant links:

Genes affected

OSR1 (HGNC:8111): (odd-skipped related transcription factor 1) Enables sequence-specific double-stranded DNA binding activity. Involved in negative regulation of ion transmembrane transporter activity; positive regulation of gastrulation; and pronephros development. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

OSR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSR1	NM_145260.3 link	c.752C>T	p.Thr251Met	missense_variant	Exon 3 of 3	ENST00000272223.3	NP_660303.1	Q8TAX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSR1	ENST00000272223.3 link	c.752C>T	p.Thr251Met	missense_variant	Exon 3 of 3	1	NM_145260.3	ENSP00000272223.2		Q8TAX0
OSR1	ENST00000487581.1 link	n.3859C>T		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111970

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.752C>T (p.T251M) alteration is located in exon 3 (coding exon 2) of the OSR1 gene. This alteration results from a C to T substitution at nucleotide position 752, causing the threonine (T) at amino acid position 251 to be replaced by a methionine (M). 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

0.38

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.77

PhyloP100

9.8

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.31

Sift

Uncertain

0.017

Sift4G

Uncertain

0.025

Polyphen

1.0

Vest4

0.62

MutPred

0.35

Loss of methylation at K250 (P = 0.0301);

MVP

0.48

ClinPred

0.83

GERP RS

5.0

Varity_R

0.20

gMVP

0.71

Mutation Taster

=47/53

disease causing

(source)

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

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NM_145260.3:c.752C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over