NM_006765.4:c.309-6T>C

Variant names:

• chr8-15650691-T-C
• rs1035972
• NM_006765.4:c.309-6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006765.4(TUSC3):​c.309-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,612,634 control chromosomes in the GnomAD database, including 101,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8064 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93301 hom.)
• Consequence: TUSC3 NM_006765.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004587
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.251
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-15650691-T-C is Benign according to our data. Variant chr8-15650691-T-C is described in ClinVar as Benign. ClinVar VariationId is 95430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.403 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	NM_006765.4	MANE Select	c.309-6T>C		splice_region intron	N/A	NP_006756.2
	TUSC3	NM_001413679.1		c.309-6T>C		splice_region intron	N/A	NP_001400608.1
	TUSC3	NM_001413684.1		c.309-6T>C		splice_region intron	N/A	NP_001400613.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.309-6T>C		splice_region intron	N/A	ENSP00000424544.1	Q13454-1
	TUSC3	ENST00000382020.8	TSL:1	c.309-6T>C		splice_region intron	N/A	ENSP00000371450.4	Q13454-2
	TUSC3	ENST00000947282.1		c.384-6T>C		splice_region intron	N/A	ENSP00000617341.1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47330 AN: 151980 Hom.: 8052 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.305

GnomAD2 exomes AF: 0.345 AC: 86643 AN: 251342 AF XY: 0.341

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.354 AC: 517033 AN: 1460534 Hom.: 93301 Cov.: 32 AF XY: 0.351 AC XY: 255077 AN XY: 726678

African (AFR) AF: 0.170 AC: 5681 AN: 33458

American (AMR) AF: 0.372 AC: 16639 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8727 AN: 26122

East Asian (EAS) AF: 0.387 AC: 15345 AN: 39670

South Asian (SAS) AF: 0.237 AC: 20458 AN: 86218

European-Finnish (FIN) AF: 0.435 AC: 23218 AN: 53346

Middle Eastern (MID) AF: 0.309 AC: 1780 AN: 5764

European-Non Finnish (NFE) AF: 0.364 AC: 403888 AN: 1110878

Other (OTH) AF: 0.353 AC: 21297 AN: 60358

GnomAD4 genome AF: 0.311 AC: 47365 AN: 152100 Hom.: 8064 Cov.: 32 AF XY: 0.314 AC XY: 23355 AN XY: 74330

African (AFR) AF: 0.177 AC: 7338 AN: 41524

American (AMR) AF: 0.335 AC: 5113 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1150 AN: 3466

East Asian (EAS) AF: 0.418 AC: 2159 AN: 5170

South Asian (SAS) AF: 0.234 AC: 1128 AN: 4816

European-Finnish (FIN) AF: 0.440 AC: 4647 AN: 10556

Middle Eastern (MID) AF: 0.300 AC: 87 AN: 290

European-Non Finnish (NFE) AF: 0.365 AC: 24781 AN: 67978

Other (OTH) AF: 0.311 AC: 656 AN: 2112

Alfa AF: 0.343 Hom.: 17192

Bravo AF: 0.302

Asia WGS AF: 0.340 AC: 1180 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.353

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Congenital disorder of glycosylation (1)
-	-	1	Intellectual disability, autosomal recessive 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.4
DANN	Benign	0.74
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.020		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: rs1035972; hg19: chr8-15508200; COSMIC: COSV65881703;