rs114532828

Variant names:

• chr12-57696268-T-C
• rs114532828
• NM_006812.4:c.481-7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006812.4(OS9):​c.481-7T>C variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00003254
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.261
• Publications: 4 publications found

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]

ENSG00000257342 (HGNC:58278):

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OS9	NM_006812.4	c.481-7T>C		splice_region_variant, intron_variant	Intron 4 of 14	ENST00000315970.12	NP_006803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OS9	ENST00000315970.12	c.481-7T>C		splice_region_variant, intron_variant	Intron 4 of 14	1	NM_006812.4	ENSP00000318165.7

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

GnomAD2 exomes AF: 0.00830 AC: 2043 AN: 246192 AF XY: 0.00750

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 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

African (AFR) AF: 0.0483 AC: 1598 AN: 33098

American (AMR) AF: 0.00796 AC: 346 AN: 43478

Ashkenazi Jewish (ASJ) AF: 0.00435 AC: 112 AN: 25720

East Asian (EAS) AF: 0.00250 AC: 99 AN: 39602

South Asian (SAS) AF: 0.00313 AC: 268 AN: 85524

European-Finnish (FIN) AF: 0.00295 AC: 157 AN: 53264

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5722

European-Non Finnish (NFE) AF: 0.00635 AC: 7013 AN: 1105240

Other (OTH) AF: 0.00912 AC: 546 AN: 59900

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

African (AFR) AF: 0.0431 AC: 1791 AN: 41518

American (AMR) AF: 0.0146 AC: 223 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5172

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00662 AC: 450 AN: 68008

Other (OTH) AF: 0.0180 AC: 38 AN: 2106

Alfa AF: 0.0114 Hom.: 16

Bravo AF: 0.0197

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.7
DANN	Benign	0.69
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs114532828; hg19: chr12-58090051;