8-15540142-A-T

Variant names:

• chr8-15540142-A-T
• rs886062762
• NM_178234.2:c.-289A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178234.2(TUSC3):​c.-289A>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 0.00000422 in 237,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TUSC3 NM_178234.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.-289A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_839952.1	Q13454-2
	TUSC3	NM_178234.2		c.-289A>T		5_prime_UTR	Exon 1 of 10	NP_839952.1	Q13454-2
	TUSC3	NM_001413670.1		c.79-82938A>T		intron	N/A	NP_001400599.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000503191.5	TSL:3	n.189+56659A>T		intron	N/A
	TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.-289A>T		upstream_gene	N/A	ENSP00000424544.1	Q13454-1
	TUSC3	ENST00000382020.8	TSL:1	c.-289A>T		upstream_gene	N/A	ENSP00000371450.4	Q13454-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 1 AN: 237194 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121752

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6126

American (AMR) AF: 0.00 AC: 0 AN: 5826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8300

East Asian (EAS) AF: 0.00 AC: 0 AN: 18574

South Asian (SAS) AF: 0.00 AC: 0 AN: 10078

European-Finnish (FIN) AF: 0.0000502 AC: 1 AN: 19914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 152038

Other (OTH) AF: 0.00 AC: 0 AN: 15142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		-0.18
PromoterAI		-0.037	Neutral

Splicing

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

Other links and lift over

dbSNP: rs886062762; hg19: chr8-15397651;