chr16-83965316-C-A

Position:

• chr16-83965316-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182981.3(OSGIN1):​c.743C>A​(p.Thr248Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000349 in 1,431,282 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: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: OSGIN1 NM_182981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

Genes affected

OSGIN1 (HGNC:30093): (oxidative stress induced growth inhibitor 1) This gene encodes an oxidative stress response protein that regulates cell death. Expression of the gene is regulated by p53 and is induced by DNA damage. The protein regulates apoptosis by inducing cytochrome c release from mitochondria. It also appears to be a key regulator of both inflammatory and anti-inflammatory molecules. The loss of this protein correlates with uncontrolled cell growth and tumor formation. Naturally occurring read-through transcription exists between this gene and the neighboring upstream malonyl-CoA decarboxylase (MLYCD) gene, but the read-through transcripts are unlikely to produce a protein product. [provided by RefSeq, Aug 2011]

NECAB2 (HGNC:23746): (N-terminal EF-hand calcium binding protein 2) The protein encoded by this gene is a neuronal calcium-binding protein that binds to and modulates the function of at least two receptors, adenosine A(2A) receptor and metabotropic glutamate receptor type 5. [provided by RefSeq, Jul 2016]

OSGIN1 (HGNC:):

ACMG classification

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, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSGIN1	NM_182981.3	c.743C>A	p.Thr248Lys	missense_variant	6/6	ENST00000393306.6	NP_892026.1
NECAB2	XM_047434240.1	c.-23+80C>A		intron_variant			XP_047290196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSGIN1	ENST00000393306.6	c.743C>A	p.Thr248Lys	missense_variant	6/6	1	NM_182981.3	ENSP00000376983.1
OSGIN1	ENST00000361711.7	c.743C>A	p.Thr248Lys	missense_variant	6/6	2		ENSP00000355374.3
OSGIN1	ENST00000343939.6	n.1375C>A		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1431282 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 708476

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000456

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 03, 2021

The c.743C>A (p.T248K) alteration is located in exon 6 (coding exon 5) of the OSGIN1 gene. This alteration results from a C to A substitution at nucleotide position 743, causing the threonine (T) at amino acid position 248 to be replaced by a lysine (K). 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	0.50
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.9	.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.76
MutPred		0.63		.;Gain of ubiquitination at T331 (P = 0.0351);.;
MVP		0.88
MPC		0.50
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.61
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-83998921;