8-15540177-C-A

Variant names:

• chr8-15540177-C-A
• rs775641863
• NM_178234.2:c.-254C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_178234.2(TUSC3):​c.-254C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 454,304 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: TUSC3 NM_178234.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.72
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.-254C>A		5_prime_UTR	Exon 1 of 10	NP_839952.1	Q13454-2
	TUSC3	NM_001413670.1		c.79-82903C>A		intron	N/A	NP_001400599.1
	TUSC3	NM_001413671.1		c.-30-82903C>A		intron	N/A	NP_001400600.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000503191.5	TSL:3	n.189+56694C>A		intron	N/A
	TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.-254C>A		upstream_gene	N/A	ENSP00000424544.1	Q13454-1
	TUSC3	ENST00000382020.8	TSL:1	c.-254C>A		upstream_gene	N/A	ENSP00000371450.4	Q13454-2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000328 AC: 99 AN: 301974 Hom.: 1 Cov.: 5 AF XY: 0.000356 AC XY: 55 AN XY: 154476

African (AFR) AF: 0.00 AC: 0 AN: 7280

American (AMR) AF: 0.000449 AC: 3 AN: 6688

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 10 AN: 9318

East Asian (EAS) AF: 0.00 AC: 0 AN: 21056

South Asian (SAS) AF: 0.000234 AC: 3 AN: 12840

European-Finnish (FIN) AF: 0.000132 AC: 3 AN: 22690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1372

European-Non Finnish (NFE) AF: 0.000360 AC: 73 AN: 202646

Other (OTH) AF: 0.000387 AC: 7 AN: 18084

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000340

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	-0.83
CADD	Benign	0.30
DANN	Benign	0.47
PhyloP100		-2.7
PromoterAI		0.24	Neutral

Splicing

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

Other links and lift over

dbSNP: rs775641863; hg19: chr8-15397686;