chr8-15540344-C-T

Variant names:

• chr8-15540344-C-T
• rs113041846
• NM_006765.4:c.-87C>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.-87C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,392,258 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., cov: 32)
  • Exomes 𝑓: 0.023 (375 hom.)
• Consequence: TUSC3 NM_006765.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.440
• Publications: 2 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=-0.53).
• BP6: Variant 8-15540344-C-T is Benign according to our data. Variant chr8-15540344-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 362306.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 = 0.0154 (2345/152274) while in subpopulation NFE AF = 0.0241 (1637/68004). AF 95% confidence interval is 0.0231. There are 34 homozygotes in GnomAd4. There are 1096 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	NM_006765.4	MANE Select	c.-87C>T		5_prime_UTR	Exon 1 of 11	NP_006756.2
	TUSC3	NM_001413679.1		c.-87C>T		5_prime_UTR	Exon 1 of 9	NP_001400608.1
	TUSC3	NM_001413684.1		c.-87C>T		5_prime_UTR	Exon 1 of 10	NP_001400613.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUSC3	ENST00000503731.6	TSL:1 MANE Select	c.-87C>T		5_prime_UTR	Exon 1 of 11	ENSP00000424544.1	Q13454-1
	TUSC3	ENST00000382020.8	TSL:1	c.-87C>T		5_prime_UTR	Exon 1 of 10	ENSP00000371450.4	Q13454-2
	TUSC3	ENST00000947282.1		c.-87C>T		5_prime_UTR	Exon 1 of 12	ENSP00000617341.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2347 AN: 152156 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00422

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0233 AC: 28856 AN: 1239984 Hom.: 375 Cov.: 30 AF XY: 0.0227 AC XY: 13677 AN XY: 601514

African (AFR) AF: 0.00349 AC: 86 AN: 24620

American (AMR) AF: 0.0104 AC: 166 AN: 15998

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 415 AN: 17646

East Asian (EAS) AF: 0.0000354 AC: 1 AN: 28240

South Asian (SAS) AF: 0.00570 AC: 326 AN: 57178

European-Finnish (FIN) AF: 0.0166 AC: 630 AN: 37860

Middle Eastern (MID) AF: 0.0120 AC: 42 AN: 3490

European-Non Finnish (NFE) AF: 0.0260 AC: 26128 AN: 1004122

Other (OTH) AF: 0.0209 AC: 1062 AN: 50830

GnomAD4 genome AF: 0.0154 AC: 2345 AN: 152274 Hom.: 34 Cov.: 32 AF XY: 0.0147 AC XY: 1096 AN XY: 74460

African (AFR) AF: 0.00421 AC: 175 AN: 41576

American (AMR) AF: 0.0126 AC: 193 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.0159 AC: 169 AN: 10622

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0241 AC: 1637 AN: 68004

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.00328 Hom.: 1

Bravo AF: 0.0148

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	0.98
PhyloP100		-0.44
PromoterAI		0.30	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113041846; hg19: chr8-15397853;