5-179820717-AG-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001142298.2(SQSTM1):c.-47-2236del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 472,122 control chromosomes in the GnomAD database, including 34 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0066 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (26 hom.)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.808

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 -10 ACMG points.

• BP6: Variant 5-179820717-AG-A is Benign according to our data. Variant chr5-179820717-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1216820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00664 (1004/151156) while in subpopulation SAS AF= 0.0104 (50/4786). AF 95% confidence interval is 0.00949. There are 8 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1005 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_001142298.2	c.-47-2236del		intron_variant
SQSTM1	NM_001142299.2	c.-47-2236del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000422245.5	c.-48+1685del		intron_variant		4
SQSTM1	ENST00000514093.5	c.-47-2236del		intron_variant		5
SQSTM1	ENST00000464493.5	n.100+16del		intron_variant, non_coding_transcript_variant		4
SQSTM1	ENST00000481335.5	n.355+335del		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1005 AN: 151046 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00577

GnomAD4 exome AF: 0.00907 AC: 2911 AN: 320966 Hom.: 26 Cov.: 4 AF XY: 0.00905 AC XY: 1518 AN XY: 167648

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00801

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00754

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00851

GnomAD4 genome AF: 0.00664 AC: 1004 AN: 151156 Hom.: 8 Cov.: 33 AF XY: 0.00642 AC XY: 474 AN XY: 73842

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00276

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.00778 Hom.: 1

Bravo AF: 0.00572

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199685457; hg19: chr5-179247717;