chr8-89924954-G-A

Position:

chr8-89924954-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001126111.3(OSGIN2):c.1072G>A(p.Ala358Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,594 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

OSGIN2
NM_001126111.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

OSGIN2 (HGNC:1355): (oxidative stress induced growth inhibitor family member 2) Predicted to enable growth factor activity. Predicted to be involved in negative regulation of cell growth. [provided by Alliance of Genome Resources, Apr 2022]

OSGIN2 links:

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
OSGIN2	NM_001126111.3 linkuse as main transcript	c.1072G>A	p.Ala358Thr	missense_variant	6/6	ENST00000451899.7	NP_001119583.1
OSGIN2	NM_004337.2 linkuse as main transcript	c.940G>A	p.Ala314Thr	missense_variant	6/6		NP_004328.1
OSGIN2	XM_011517287.4 linkuse as main transcript	c.940G>A	p.Ala314Thr	missense_variant	6/6		XP_011515589.1
OSGIN2	XM_011517288.4 linkuse as main transcript	c.541G>A	p.Ala181Thr	missense_variant	3/3		XP_011515590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN2	ENST00000451899.7 linkuse as main transcript	c.1072G>A	p.Ala358Thr	missense_variant	6/6	1	NM_001126111.3	ENSP00000396445		Q9Y236-2
OSGIN2	ENST00000297438.6 linkuse as main transcript	c.940G>A	p.Ala314Thr	missense_variant	6/6	1		ENSP00000297438	P1	Q9Y236-1
OSGIN2	ENST00000647849.1 linkuse as main transcript	c.940G>A	p.Ala314Thr	missense_variant	6/6			ENSP00000497119	P1	Q9Y236-1
NBN	ENST00000697292.1 linkuse as main transcript	c.*426C>T		3_prime_UTR_variant	17/17			ENSP00000513229	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250670

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461594

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2023

The c.1072G>A (p.A358T) alteration is located in exon 6 (coding exon 6) of the OSGIN2 gene. This alteration results from a G to A substitution at nucleotide position 1072, causing the alanine (A) at amino acid position 358 to be replaced by a threonine (T). 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

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.5

.;D;D

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.0060

.;D;D

Polyphen

1.0

D;D;D

Vest4

0.86, 0.89

MutPred

0.78

Loss of stability (P = 0.1157);Loss of stability (P = 0.1157);.;

MVP

0.59

MPC

1.1

ClinPred

0.98

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over