5-179820902-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000626660.1(SQSTM1):c.-35G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,473,186 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (35 hom.)
• Consequence: SQSTM1 ENST00000626660.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.98

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-179820902-G-C is Benign according to our data. Variant chr5-179820902-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 353151.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 = 0.0138 (2094/152286) while in subpopulation AFR AF= 0.0438 (1819/41574). AF 95% confidence interval is 0.0421. There are 45 homozygotes in gnomad4. There are 1007 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 2085 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_001142298.2	c.-47-2056G>C		intron_variant
SQSTM1	NM_001142299.2	c.-47-2056G>C		intron_variant
SQSTM1	NM_003900.5			upstream_gene_variant		ENST00000389805.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9			upstream_gene_variant		1	NM_003900.5	P1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2085 AN: 152178 Hom.: 45 Cov.: 34

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00276 AC: 327 AN: 118572 Hom.: 5 AF XY: 0.00245 AC XY: 168 AN XY: 68496

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000975

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00212 AC: 2797 AN: 1320900 Hom.: 35 Cov.: 30 AF XY: 0.00199 AC XY: 1286 AN XY: 647604

Gnomad4 AFR exome AF: 0.0462

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00451

GnomAD4 genome AF: 0.0138 AC: 2094 AN: 152286 Hom.: 45 Cov.: 34 AF XY: 0.0135 AC XY: 1007 AN XY: 74460

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00229 Hom.: 2

Bravo AF: 0.0156

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bone Paget disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.6
Dann	Benign	0.39

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: rs189132632; hg19: chr5-179247902;