rs796052213

Positions:

• chr5-179833749-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_Strong PP5 BS2_Supporting

The NM_003900.5(SQSTM1):​c.1132A>T​(p.Lys378Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,856 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SQSTM1 NM_003900.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.46

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.144 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 5-179833749-A-T is Pathogenic according to our data. Variant chr5-179833749-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 202210.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.1132A>T	p.Lys378Ter	stop_gained	7/8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.880A>T	p.Lys294Ter	stop_gained	8/9		NP_001135770.1
SQSTM1	NM_001142299.2	c.880A>T	p.Lys294Ter	stop_gained	8/9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.1132A>T	p.Lys378Ter	stop_gained	7/8	1	NM_003900.5	ENSP00000374455	P1
SQSTM1	ENST00000360718.5	c.880A>T	p.Lys294Ter	stop_gained	6/7	1		ENSP00000353944
SQSTM1	ENST00000510187.5	c.950+522A>T		intron_variant		5		ENSP00000424477

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

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: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Paget disease of bone 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	47
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D
Vest4		0.95
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs796052213; hg19: chr5-179260749;