rs2604357

Variant names:

• chr8-15743653-C-G
• rs2604357
• NM_006765.4:c.937+41C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-15743653-C-G
• chr8-15743653-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006765.4(TUSC3):​c.937+41C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,599,688 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (172 hom.)
• Consequence: TUSC3 NM_006765.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.905
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-15743653-C-G is Benign according to our data. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-15743653-C-G is described in CliVar as Likely_benign. Clinvar id is 1187727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0098 (1491/152204) while in subpopulation SAS AF = 0.0249 (120/4810). AF 95% confidence interval is 0.0213. There are 9 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUSC3	NM_006765.4	c.937+41C>G		intron_variant	Intron 8 of 10	ENST00000503731.6	NP_006756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUSC3	ENST00000503731.6	c.937+41C>G		intron_variant	Intron 8 of 10	1	NM_006765.4	ENSP00000424544.1

Frequencies

GnomAD3 genomes AF: 0.00980 AC: 1490 AN: 152086 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.00689

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0147 AC: 3675 AN: 249528 AF XY: 0.0164

Gnomad AFR exome AF: 0.00186

Gnomad AMR exome AF: 0.00756

Gnomad ASJ exome AF: 0.0406

Gnomad EAS exome AF: 0.0264

Gnomad FIN exome AF: 0.00625

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0114 AC: 16533 AN: 1447484 Hom.: 172 Cov.: 27 AF XY: 0.0124 AC XY: 8918 AN XY: 720902

African (AFR) AF: 0.00242 AC: 80 AN: 33122

American (AMR) AF: 0.00828 AC: 370 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 1030 AN: 26048

East Asian (EAS) AF: 0.0161 AC: 639 AN: 39598

South Asian (SAS) AF: 0.0326 AC: 2804 AN: 85930

European-Finnish (FIN) AF: 0.00651 AC: 347 AN: 53294

Middle Eastern (MID) AF: 0.0324 AC: 186 AN: 5732

European-Non Finnish (NFE) AF: 0.00937 AC: 10300 AN: 1099152

Other (OTH) AF: 0.0130 AC: 777 AN: 59904

GnomAD4 genome AF: 0.00980 AC: 1491 AN: 152204 Hom.: 9 Cov.: 33 AF XY: 0.00970 AC XY: 722 AN XY: 74404

African (AFR) AF: 0.00234 AC: 97 AN: 41530

American (AMR) AF: 0.0132 AC: 201 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3470

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5180

South Asian (SAS) AF: 0.0249 AC: 120 AN: 4810

European-Finnish (FIN) AF: 0.00689 AC: 73 AN: 10590

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 716 AN: 68020

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.00984 Hom.: 6

Bravo AF: 0.0108

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.93
DANN	Benign	0.58
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2604357; hg19: chr8-15601162;