5-179820919-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003900.5(SQSTM1):c.-18G>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 0.000408 in 1,520,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: SQSTM1 NM_003900.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.908

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS2: High AC in GnomAd at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.-18G>A		5_prime_UTR_variant	1/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.-47-2039G>A		intron_variant
SQSTM1	NM_001142299.2	c.-47-2039G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.-18G>A		5_prime_UTR_variant	1/8	1	NM_003900.5	P1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000258 AC: 42 AN: 162828 Hom.: 0 AF XY: 0.000269 AC XY: 25 AN XY: 92894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000776

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000302

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000427

Gnomad OTH exome AF: 0.000246

GnomAD4 exome AF: 0.000418 AC: 572 AN: 1367966 Hom.: 1 Cov.: 31 AF XY: 0.000402 AC XY: 271 AN XY: 674008

Gnomad4 AFR exome AF: 0.0000353

Gnomad4 AMR exome AF: 0.000189

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000228

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000483

Gnomad4 OTH exome AF: 0.000512

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74456

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.000468

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paget disease of bone 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.97
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs370874635; hg19: chr5-179247919;