8-15540158-G-A

Position:

• chr8-15540158-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_178234.2(TUSC3):​c.-273G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 417,842 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (46 hom.)
• Consequence: TUSC3 NM_178234.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.84

Genes affected

TUSC3 (HGNC:30242): (tumor suppressor candidate 3) This gene encodes a protein that has been associated with several biological functions including cellular magnesium uptake, protein glycosylation and embryonic development. This protein localizes to the endoplasmic reticulum and acts as a component of the oligosaccharyl transferase complex which is responsible for N-linked protein glycosylation. This gene is a candidate tumor suppressor gene. Homozygous mutations in this gene are associated with autosomal recessive nonsyndromic mental retardation-7 and in the proliferation and invasiveness of several cancers including metastatic pancreatic cancer, ovarian cancer and glioblastoma multiform. [provided by RefSeq, Oct 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-15540158-G-A is Benign according to our data. Variant chr8-15540158-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 362295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUSC3	NM_178234.2	c.-273G>A		5_prime_UTR_variant	1/10
TUSC3	NM_001413669.1	c.-30-82922G>A		intron_variant
TUSC3	NM_001413670.1	c.79-82922G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUSC3	ENST00000503191.5	n.189+56675G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 506 AN: 152220 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0367

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00598 AC: 1589 AN: 265506 Hom.: 46 AF XY: 0.00570 AC XY: 777 AN XY: 136344

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.00804

Gnomad4 ASJ exome AF: 0.00247

Gnomad4 EAS exome AF: 0.0683

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.000504

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152336 Hom.: 7 Cov.: 32 AF XY: 0.00397 AC XY: 296 AN XY: 74488

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0370

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000902 Hom.: 0

Bravo AF: 0.00332

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.21
DANN	Benign	0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3810773; hg19: chr8-15397667;