8-15540344-C-T

Position:

• chr8-15540344-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000503731(TUSC3):​c.-87C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,392,258 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., cov: 32)
  • Exomes 𝑓: 0.023 (375 hom.)
• Consequence: TUSC3 ENST00000503731 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.440

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]

TUSC3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-15540344-C-T is Benign according to our data. Variant chr8-15540344-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 362306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2345/152274) while in subpopulation NFE AF= 0.0241 (1637/68004). AF 95% confidence interval is 0.0231. There are 34 homozygotes in gnomad4. There are 1096 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUSC3	NM_006765.4	c.-87C>T		5_prime_UTR_variant	1/11	ENST00000503731.6	NP_006756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUSC3	ENST00000503731	c.-87C>T		5_prime_UTR_variant	1/11	1	NM_006765.4	ENSP00000424544.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2347 AN: 152156 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0233 AC: 28856 AN: 1239984 Hom.: 375 Cov.: 30 AF XY: 0.0227 AC XY: 13677 AN XY: 601514

Gnomad4 AFR exome AF: 0.00349

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.0000354

Gnomad4 SAS exome AF: 0.00570

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.0260

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0154 AC: 2345 AN: 152274 Hom.: 34 Cov.: 32 AF XY: 0.0147 AC XY: 1096 AN XY: 74460

Gnomad4 AFR AF: 0.00421

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00328 Hom.: 1

Bravo AF: 0.0148

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2020	- -

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	-0.53
CADD	Benign	15
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113041846; hg19: chr8-15397853;