rs11545035

Positions:

• chr8-15623134-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006765.4(TUSC3):​c.193A>G​(p.Ile65Val) variant causes a missense change. The variant allele was found at a frequency of 0.00703 in 1,613,952 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (51 hom.)
• Consequence: TUSC3 NM_006765.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.32

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00399366).
• BP6: Variant 8-15623134-A-G is Benign according to our data. Variant chr8-15623134-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00584 (890/152328) while in subpopulation NFE AF= 0.00805 (548/68034). AF 95% confidence interval is 0.0075. There are 5 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUSC3	NM_006765.4	c.193A>G	p.Ile65Val	missense_variant	2/11	ENST00000503731.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUSC3	ENST00000503731.6	c.193A>G	p.Ile65Val	missense_variant	2/11	1	NM_006765.4	A1

Frequencies

GnomAD3 genomes AF: 0.00585 AC: 890 AN: 152210 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00807

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00664 AC: 1669 AN: 251258 Hom.: 7 AF XY: 0.00684 AC XY: 929 AN XY: 135780

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.00857

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00716 AC: 10460 AN: 1461624 Hom.: 51 Cov.: 31 AF XY: 0.00706 AC XY: 5135 AN XY: 727090

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.0307

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00642

Gnomad4 NFE exome AF: 0.00768

Gnomad4 OTH exome AF: 0.00727

GnomAD4 genome AF: 0.00584 AC: 890 AN: 152328 Hom.: 5 Cov.: 32 AF XY: 0.00546 AC XY: 407 AN XY: 74490

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00687

Gnomad4 NFE AF: 0.00805

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00827 Hom.: 10

Bravo AF: 0.00597

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00646 AC: 784

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00901

EpiControl AF: 0.00913

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TUSC3: BP4, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2015	- -

Intellectual disability, autosomal recessive 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TUSC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital disorder of glycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.56
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0040	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.5	N;.;.;N;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.34	N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.11
MVP		0.18
MPC		0.22
ClinPred		0.019	T
GERP RS		0.17
Varity_R		0.12
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs11545035; hg19: chr8-15480643;