8-15540311-C-T

Variant names:

• chr8-15540311-C-T
• rs12550009
• NM_006765.4:c.-120C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006765.4(TUSC3):​c.-120C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,323,854 control chromosomes in the GnomAD database, including 27,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3137 hom., cov: 32)
  • Exomes 𝑓: 0.20 (24627 hom.)
• Consequence: TUSC3 NM_006765.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.162

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 8-15540311-C-T is Benign according to our data. Variant chr8-15540311-C-T is described in ClinVar as [Benign]. Clinvar id is 362304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUSC3	NM_006765.4	c.-120C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	ENST00000503731.6	NP_006756.2
TUSC3	NM_006765.4	c.-120C>T		5_prime_UTR_variant	Exon 1 of 11	ENST00000503731.6	NP_006756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUSC3	ENST00000503731	c.-120C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	1	NM_006765.4	ENSP00000424544.1
TUSC3	ENST00000503731	c.-120C>T		5_prime_UTR_variant	Exon 1 of 11	1	NM_006765.4	ENSP00000424544.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30942 AN: 152042 Hom.: 3137 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.203 AC: 237953 AN: 1171696 Hom.: 24627 Cov.: 20 AF XY: 0.205 AC XY: 116100 AN XY: 566884

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.268

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.203 AC: 30951 AN: 152158 Hom.: 3137 Cov.: 32 AF XY: 0.205 AC XY: 15222 AN XY: 74394

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.200

Alfa AF: 0.103 Hom.: 148

Bravo AF: 0.206

Asia WGS AF: 0.219 AC: 760 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital disorder of glycosylation Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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

Other links and lift over

dbSNP: rs12550009; hg19: chr8-15397820; COSMIC: COSV65881220;