5-179820912-G-A

Variant names:

• chr5-179820912-G-A
• rs74523483
• NM_003900.5:c.-25G>A

Variant summary

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

The NM_003900.5(SQSTM1):​c.-25G>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 0.00225 in 1,498,294 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (41 hom.)
• Consequence: SQSTM1 NM_003900.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0240

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=-0.67).
• BP6: Variant 5-179820912-G-A is Benign according to our data. Variant chr5-179820912-G-A is described in ClinVar as [Benign]. Clinvar id is 353152.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1862/152288) while in subpopulation AFR AF= 0.0427 (1777/41568). AF 95% confidence interval is 0.0411. There are 36 homozygotes in gnomad4. There are 873 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1862 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.-25G>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.-47-2046G>A		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2046G>A		intron_variant	Intron 2 of 8		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805	c.-25G>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 152180 Hom.: 35 Cov.: 34

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00178 AC: 260 AN: 145928 Hom.: 3 AF XY: 0.00125 AC XY: 105 AN XY: 83846

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000923

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000603

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00112 AC: 1513 AN: 1346006 Hom.: 41 Cov.: 31 AF XY: 0.00101 AC XY: 667 AN XY: 662358

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000782

Gnomad4 FIN exome AF: 0.0000269

Gnomad4 NFE exome AF: 0.0000265

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0122 AC: 1862 AN: 152288 Hom.: 36 Cov.: 34 AF XY: 0.0117 AC XY: 873 AN XY: 74462

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00690 Hom.: 5

Bravo AF: 0.0134

Asia WGS AF: 0.00232 AC: 8 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paget disease of bone 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.2
DANN	Benign	0.90
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: rs74523483; hg19: chr5-179247912;