chr8-15540323-G-A

Variant names:

• chr8-15540323-G-A
• rs563436944
• NM_006765.4:c.-108G>A

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.-108G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,353,922 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (13 hom.)
• Consequence: TUSC3 NM_006765.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.592
• Publications: 1 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=-0.67).
• BP6: Variant 8-15540323-G-A is Benign according to our data. Variant chr8-15540323-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 362305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00778 (1184/152274) while in subpopulation AFR AF = 0.0257 (1068/41584). AF 95% confidence interval is 0.0244. There are 12 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.-108G>A		5_prime_UTR	Exon 1 of 11	NP_006756.2
	TUSC3	NM_001413679.1		c.-108G>A		5_prime_UTR	Exon 1 of 9	NP_001400608.1
	TUSC3	NM_001413684.1		c.-108G>A		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.-108G>A		5_prime_UTR	Exon 1 of 11	ENSP00000424544.1	Q13454-1
	TUSC3	ENST00000382020.8	TSL:1	c.-108G>A		5_prime_UTR	Exon 1 of 10	ENSP00000371450.4	Q13454-2
	TUSC3	ENST00000947282.1		c.-108G>A		5_prime_UTR	Exon 1 of 12	ENSP00000617341.1

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1182 AN: 152156 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.000964 AC: 1158 AN: 1201648 Hom.: 13 Cov.: 27 AF XY: 0.000876 AC XY: 509 AN XY: 581246

African (AFR) AF: 0.0323 AC: 758 AN: 23468

American (AMR) AF: 0.00247 AC: 28 AN: 11348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16562

East Asian (EAS) AF: 0.00 AC: 0 AN: 27718

South Asian (SAS) AF: 0.000250 AC: 13 AN: 52070

European-Finnish (FIN) AF: 0.0000587 AC: 2 AN: 34094

Middle Eastern (MID) AF: 0.00539 AC: 18 AN: 3338

European-Non Finnish (NFE) AF: 0.000240 AC: 236 AN: 983778

Other (OTH) AF: 0.00209 AC: 103 AN: 49272

GnomAD4 genome AF: 0.00778 AC: 1184 AN: 152274 Hom.: 12 Cov.: 32 AF XY: 0.00756 AC XY: 563 AN XY: 74452

African (AFR) AF: 0.0257 AC: 1068 AN: 41584

American (AMR) AF: 0.00516 AC: 79 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68000

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00659 Hom.: 1

Bravo AF: 0.00861

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		-0.59
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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: rs563436944; hg19: chr8-15397832;