NM_006765.4:c.308+12659G>T

Variant names:

• chr8-15635908-G-T
• rs4258002
• NM_006765.4:c.308+12659G>T

Variant summary

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

The NM_006765.4(TUSC3):​c.308+12659G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,102 control chromosomes in the GnomAD database, including 3,299 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 0.20 (3299 hom., cov: 32)
• Consequence: TUSC3 NM_006765.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.455
• Publications: 7 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.346 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.308+12659G>T		intron	N/A	NP_006756.2
	TUSC3	NM_001413679.1		c.308+12659G>T		intron	N/A	NP_001400608.1
	TUSC3	NM_001413684.1		c.308+12659G>T		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.308+12659G>T		intron	N/A	ENSP00000424544.1
	TUSC3	ENST00000382020.8	TSL:1	c.308+12659G>T		intron	N/A	ENSP00000371450.4
	TUSC3	ENST00000506802.5	TSL:5	c.308+12659G>T		intron	N/A	ENSP00000425777.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29633 AN: 151984 Hom.: 3295 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.204

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

GnomAD4 genome AF: 0.195 AC: 29671 AN: 152102 Hom.: 3299 Cov.: 32 AF XY: 0.198 AC XY: 14733 AN XY: 74342

African (AFR) AF: 0.270 AC: 11203 AN: 41494

American (AMR) AF: 0.244 AC: 3729 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 691 AN: 3466

East Asian (EAS) AF: 0.231 AC: 1190 AN: 5160

South Asian (SAS) AF: 0.361 AC: 1732 AN: 4804

European-Finnish (FIN) AF: 0.0745 AC: 789 AN: 10596

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9649 AN: 67988

Other (OTH) AF: 0.202 AC: 426 AN: 2108

Alfa AF: 0.168 Hom.: 6491

Bravo AF: 0.206

Asia WGS AF: 0.278 AC: 969 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.62
DANN	Benign	0.49
PhyloP100		-0.46
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: rs4258002; hg19: chr8-15493417;