chr8-15540241-C-T

Variant names:

• chr8-15540241-C-T
• rs573872013
• ENST00000382020.8:c.-190C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_178234.2(TUSC3):​c.-190C>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 0.00257 in 809,352 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (2 hom.)
• Consequence: TUSC3 NM_178234.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00174 (265/152300) while in subpopulation NFE AF = 0.00312 (212/68028). AF 95% confidence interval is 0.00277. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178234.2. 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.-190C>T		5_prime_UTR	Exon 1 of 10	NP_839952.1	Q13454-2
	TUSC3	NM_001413670.1		c.79-82839C>T		intron	N/A	NP_001400599.1
	TUSC3	NM_001413671.1		c.-30-82839C>T		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.-190C>T		5_prime_UTR	Exon 1 of 10	ENSP00000371450.4	Q13454-2
	TUSC3	ENST00000877722.1		c.-190C>T		5_prime_UTR	Exon 1 of 11	ENSP00000547781.1
	TUSC3	ENST00000928815.1		c.-190C>T		5_prime_UTR	Exon 1 of 10	ENSP00000598874.1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00277 AC: 1817 AN: 657052 Hom.: 2 Cov.: 9 AF XY: 0.00270 AC XY: 882 AN XY: 326242

African (AFR) AF: 0.000595 AC: 8 AN: 13454

American (AMR) AF: 0.00113 AC: 9 AN: 7958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12398

East Asian (EAS) AF: 0.00 AC: 0 AN: 24164

South Asian (SAS) AF: 0.00 AC: 0 AN: 29608

European-Finnish (FIN) AF: 0.000744 AC: 20 AN: 26890

Middle Eastern (MID) AF: 0.00136 AC: 3 AN: 2200

European-Non Finnish (NFE) AF: 0.00339 AC: 1728 AN: 509696

Other (OTH) AF: 0.00160 AC: 49 AN: 30684

GnomAD4 genome AF: 0.00174 AC: 265 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74456

African (AFR) AF: 0.000481 AC: 20 AN: 41588

American (AMR) AF: 0.00111 AC: 17 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00206

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
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		1.1
PromoterAI		0.17	Neutral
Mutation Taster		=295/5	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs573872013; hg19: chr8-15397750;