rs155788

Positions:

• chr5-179833528-T-C
• chr5-179833528-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003900.5(SQSTM1):​c.970-59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,577,672 control chromosomes in the GnomAD database, including 13,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (4294 hom., cov: 33)
  • Exomes 𝑓: 0.099 (9321 hom.)
• Consequence: SQSTM1 NM_003900.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.238

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-179833528-T-C is Benign according to our data. Variant chr5-179833528-T-C is described in ClinVar as [Benign]. Clinvar id is 1221180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.970-59T>C		intron_variant		ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.718-59T>C		intron_variant			NP_001135770.1
SQSTM1	NM_001142299.2	c.718-59T>C		intron_variant			NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.970-59T>C		intron_variant		1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.718-59T>C		intron_variant		1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.950+301T>C		intron_variant		5		ENSP00000424477.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28019 AN: 152078 Hom.: 4280 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0564

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0880

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.0991 AC: 141198 AN: 1425476 Hom.: 9321 Cov.: 28 AF XY: 0.0964 AC XY: 68533 AN XY: 710650

Gnomad4 AFR exome AF: 0.439

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.0560

Gnomad4 FIN exome AF: 0.0535

Gnomad4 NFE exome AF: 0.0911

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.184 AC: 28078 AN: 152196 Hom.: 4294 Cov.: 33 AF XY: 0.179 AC XY: 13318 AN XY: 74422

Gnomad4 AFR AF: 0.423

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0562

Gnomad4 FIN AF: 0.0517

Gnomad4 NFE AF: 0.0880

Gnomad4 OTH AF: 0.169

Alfa AF: 0.105 Hom.: 1558

Bravo AF: 0.202

Asia WGS AF: 0.103 AC: 361 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.56
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9

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: rs155788; hg19: chr5-179260528; COSMIC: COSV52976302; COSMIC: COSV52976302;