ENST00000382020.8:c.-173_-172delCT

Variant names:

• chr8-15540255-GCT-G
• rs761637643
• ENST00000382020.8:c.-173_-172delCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The ENST00000382020.8(TUSC3):​c.-173_-172delCT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 877,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: TUSC3 ENST00000382020.8 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000357 (259/725696) while in subpopulation NFE AF = 0.000445 (254/570370). AF 95% confidence interval is 0.0004. There are 0 homozygotes in GnomAdExome4. There are 122 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000382020.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	NM_178234.2		c.-173_-172delCT		5_prime_UTR	Exon 1 of 10	NP_839952.1	Q13454-2
	TUSC3	NM_001413670.1		c.79-82822_79-82821delCT		intron	N/A	NP_001400599.1
	TUSC3	NM_001413671.1		c.-30-82822_-30-82821delCT		intron	N/A	NP_001400600.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000382020.8	TSL:1	c.-173_-172delCT		5_prime_UTR	Exon 1 of 10	ENSP00000371450.4	Q13454-2
	TUSC3	ENST00000947283.1		c.-173_-172delCT		5_prime_UTR	Exon 1 of 11	ENSP00000617342.1
	TUSC3	ENST00000877722.1		c.-173_-172delCT		5_prime_UTR	Exon 1 of 11	ENSP00000547781.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000357 AC: 259 AN: 725696 Hom.: 0 AF XY: 0.000340 AC XY: 122 AN XY: 358744

African (AFR) AF: 0.0000679 AC: 1 AN: 14722

American (AMR) AF: 0.00 AC: 0 AN: 8166

Ashkenazi Jewish (ASJ) AF: 0.0000776 AC: 1 AN: 12882

East Asian (EAS) AF: 0.00 AC: 0 AN: 24566

South Asian (SAS) AF: 0.00 AC: 0 AN: 32404

European-Finnish (FIN) AF: 0.0000366 AC: 1 AN: 27324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2348

European-Non Finnish (NFE) AF: 0.000445 AC: 254 AN: 570370

Other (OTH) AF: 0.0000608 AC: 2 AN: 32914

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74338

African (AFR) AF: 0.000145 AC: 6 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000174

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=299/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs761637643; hg19: chr8-15397764;