NM_006765.4:c.38C>T

Variant names:

• chr8-15540468-C-T
• rs200808372
• NM_006765.4:c.38C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_006765.4(TUSC3):​c.38C>T​(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000676 in 1,605,990 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A13A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (2 hom.)
• Consequence: TUSC3 NM_006765.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 B:1
• Conservation: PhyloP100: 1.42
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020807922).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000545 (83/152228) while in subpopulation NFE AF = 0.000882 (60/68036). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.38C>T	p.Ala13Val	missense	Exon 1 of 11	NP_006756.2
	TUSC3	NM_001413679.1		c.38C>T	p.Ala13Val	missense	Exon 1 of 9	NP_001400608.1
	TUSC3	NM_001413684.1		c.38C>T	p.Ala13Val	missense	Exon 1 of 10	NP_001400613.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.38C>T	p.Ala13Val	missense	Exon 1 of 11	ENSP00000424544.1
	TUSC3	ENST00000382020.8	TSL:1	c.38C>T	p.Ala13Val	missense	Exon 1 of 10	ENSP00000371450.4
	TUSC3	ENST00000506802.5	TSL:5	c.38C>T	p.Ala13Val	missense	Exon 1 of 9	ENSP00000425777.1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000587 AC: 135 AN: 229794 AF XY: 0.000695

Gnomad AFR exome AF: 0.000149

Gnomad AMR exome AF: 0.000300

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000526

Gnomad NFE exome AF: 0.000890

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000690 AC: 1003 AN: 1453762 Hom.: 2 Cov.: 31 AF XY: 0.000700 AC XY: 506 AN XY: 723060

African (AFR) AF: 0.000122 AC: 4 AN: 32662

American (AMR) AF: 0.000250 AC: 11 AN: 44082

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 29 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39266

South Asian (SAS) AF: 0.000340 AC: 29 AN: 85326

European-Finnish (FIN) AF: 0.000290 AC: 15 AN: 51712

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5642

European-Non Finnish (NFE) AF: 0.000781 AC: 866 AN: 1109118

Other (OTH) AF: 0.000650 AC: 39 AN: 60032

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74368

African (AFR) AF: 0.000169 AC: 7 AN: 41464

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4836

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68036

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.000686 Hom.: 0

Bravo AF: 0.000548

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000480 AC: 58

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 7 Uncertain:2

Jul 05, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the TUSC3 protein (p.Ala13Val). This variant is present in population databases (rs200808372, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of TUSC3-related conditions (PMID: 28820871). ClinVar contains an entry for this variant (Variation ID: 547986). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 03, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with ADHD and a clinical diagnosis of fetal alcohol syndrome (de la Morena-Barrio et al., 2018); This variant is associated with the following publications: (PMID: Kubo2019[article], 33206719, 28820871)

Inborn genetic diseases Uncertain:1

Mar 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>T (p.A13V) alteration is located in exon 1 (coding exon 1) of the TUSC3 gene. This alteration results from a C to T substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a valine (V). The p.A13V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Congenital disorder of glycosylation Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

TUSC3-related disorder Benign:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.19
Sift	Benign	0.34	T
Sift4G	Benign	0.63	T
Polyphen		0.0030	B
Vest4		0.38
MVP		0.27
MPC		0.26
ClinPred		0.012	T
GERP RS		2.4
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.066
gMVP		0.60
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs200808372; hg19: chr8-15397977;