rs4831760

Variant names:

• chr8-15675076-T-C
• rs4831760
• NM_006765.4:c.798+1240T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006765.4(TUSC3):​c.798+1240T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 151,824 control chromosomes in the GnomAD database, including 7,078 homozygotes. 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: 𝑓 0.30 (7078 hom., cov: 31)
• Consequence: TUSC3 NM_006765.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 15 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: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006765.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	NM_006765.4	MANE Select	c.798+1240T>C		intron	N/A	NP_006756.2
	TUSC3	NM_001413679.1		c.798+1240T>C		intron	N/A	NP_001400608.1
	TUSC3	NM_001413684.1		c.798+1240T>C		intron	N/A	NP_001400613.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.798+1240T>C		intron	N/A	ENSP00000424544.1
	TUSC3	ENST00000382020.8	TSL:1	c.798+1240T>C		intron	N/A	ENSP00000371450.4
	TUSC3	ENST00000506802.5	TSL:5	c.798+1240T>C		intron	N/A	ENSP00000425777.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45315 AN: 151708 Hom.: 7077 Cov.: 31

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0866

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.287

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.299 AC: 45342 AN: 151824 Hom.: 7078 Cov.: 31 AF XY: 0.294 AC XY: 21796 AN XY: 74190

African (AFR) AF: 0.362 AC: 15002 AN: 41420

American (AMR) AF: 0.225 AC: 3424 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 845 AN: 3470

East Asian (EAS) AF: 0.0862 AC: 444 AN: 5148

South Asian (SAS) AF: 0.149 AC: 720 AN: 4822

European-Finnish (FIN) AF: 0.337 AC: 3556 AN: 10548

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20489 AN: 67882

Other (OTH) AF: 0.283 AC: 595 AN: 2104

Alfa AF: 0.292 Hom.: 22390

Bravo AF: 0.293

Asia WGS AF: 0.115 AC: 403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.0
DANN	Benign	0.42
PhyloP100		-0.070
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4831760; hg19: chr8-15532585;