5-179820766-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001142298.2(SQSTM1):c.-47-2192T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 552,402 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 34)
  • Exomes 𝑓: 0.00077 (7 hom.)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0790

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=-0.72).
• BP6: Variant 5-179820766-T-C is Benign according to our data. Variant chr5-179820766-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1217548.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0078 (1180/151192) while in subpopulation AFR AF= 0.027 (1111/41110). AF 95% confidence interval is 0.0257. There are 16 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 1177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_001142298.2	c.-47-2192T>C		intron_variant
SQSTM1	NM_001142299.2	c.-47-2192T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000422245.5	c.-48+1729T>C		intron_variant		4
SQSTM1	ENST00000514093.5	c.-47-2192T>C		intron_variant		5
SQSTM1	ENST00000464493.5	n.100+60T>C		intron_variant, non_coding_transcript_variant		4
SQSTM1	ENST00000481335.5	n.355+379T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00779 AC: 1177 AN: 151076 Hom.: 16 Cov.: 34

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00624

GnomAD4 exome AF: 0.000768 AC: 308 AN: 401210 Hom.: 7 Cov.: 5 AF XY: 0.000588 AC XY: 123 AN XY: 209110

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.00263

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000926

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000340

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00780 AC: 1180 AN: 151192 Hom.: 16 Cov.: 34 AF XY: 0.00783 AC XY: 579 AN XY: 73906

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00610 Hom.: 1

Bravo AF: 0.00897

Asia WGS AF: 0.00115 AC: 4 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

Mar 17, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	4.5
Dann	Benign	0.64

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: rs534068817; hg19: chr5-179247766;