5-179823038-C-T

Variant names:

• chr5-179823038-C-T
• rs886039782
• NM_003900.5:c.286C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_003900.5(SQSTM1):​c.286C>T​(p.Arg96*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SQSTM1 NM_003900.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.72

Genes affected

SQSTM1 (HGNC:11280): (sequestosome 1) This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-179823038-C-T is Pathogenic according to our data. Variant chr5-179823038-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.286C>T	p.Arg96*	stop_gained	Exon 2 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.34C>T	p.Arg12*	stop_gained	Exon 3 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.34C>T	p.Arg12*	stop_gained	Exon 3 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.286C>T	p.Arg96*	stop_gained	Exon 2 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461786 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset Pathogenic:3

Mar 20, 2024

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PS1,PP5 -

Oct 10, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Pathogenic:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg96*) in the SQSTM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SQSTM1 are known to be pathogenic (PMID: 27545679, 29959261). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP) (PMID: 27545679). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265782). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.90, 0.94, 0.87
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs886039782; hg19: chr5-179250038; COSMIC: COSV62434714; COSMIC: COSV62434714;