12-57696268-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006812.4(OS9):c.481-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,603,764 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (43 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (79 hom.)
• Consequence: OS9 NM_006812.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003254
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.261

Genes affected

OS9 (HGNC:16994): (OS9 endoplasmic reticulum lectin) This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-57696268-T-C is Benign according to our data. Variant chr12-57696268-T-C is described in ClinVar as [Benign]. Clinvar id is 776728.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0171 (2609/152216) while in subpopulation AFR AF= 0.0431 (1791/41518). AF 95% confidence interval is 0.0415. There are 43 homozygotes in gnomad4. There are 1216 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OS9	NM_006812.4	c.481-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000315970.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OS9	ENST00000315970.12	c.481-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006812.4	P4
	ENST00000549477.1	n.535-1972A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2609 AN: 152098 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00662

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00830 AC: 2043 AN: 246192 Hom.: 27 AF XY: 0.00750 AC XY: 999 AN XY: 133198

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.00675

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00412

Gnomad SAS exome AF: 0.00335

Gnomad FIN exome AF: 0.00266

Gnomad NFE exome AF: 0.00682

Gnomad OTH exome AF: 0.00754

GnomAD4 exome AF: 0.00702 AC: 10197 AN: 1451548 Hom.: 79 Cov.: 30 AF XY: 0.00676 AC XY: 4881 AN XY: 722110

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.00796

Gnomad4 ASJ exome AF: 0.00435

Gnomad4 EAS exome AF: 0.00250

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.00295

Gnomad4 NFE exome AF: 0.00635

Gnomad4 OTH exome AF: 0.00912

GnomAD4 genome AF: 0.0171 AC: 2609 AN: 152216 Hom.: 43 Cov.: 31 AF XY: 0.0163 AC XY: 1216 AN XY: 74422

Gnomad4 AFR AF: 0.0431

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00662

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0111 Hom.: 14

Bravo AF: 0.0197

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	8.7
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs114532828; hg19: chr12-58090051;