5-179820766-T-C

Variant names:

• chr5-179820766-T-C
• rs534068817
• NM_001142298.2:c.-47-2192T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

SQSTM1 Gene-Disease associations (from GenCC):

• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• behavioral variant of frontotemporal dementia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000301422 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-47-2192T>C		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2192T>C		intron_variant	Intron 2 of 8		NP_001135771.1
SQSTM1	NM_003900.5	c.-171T>C		upstream_gene_variant		ENST00000389805.9	NP_003891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.-171T>C		upstream_gene_variant		1	NM_003900.5	ENSP00000374455.4

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

African (AFR) AF: 0.0270 AC: 224 AN: 8310

American (AMR) AF: 0.00263 AC: 22 AN: 8376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11320

East Asian (EAS) AF: 0.00 AC: 0 AN: 23310

South Asian (SAS) AF: 0.0000926 AC: 3 AN: 32382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28352

Middle Eastern (MID) AF: 0.00113 AC: 2 AN: 1772

European-Non Finnish (NFE) AF: 0.0000340 AC: 9 AN: 264606

Other (OTH) AF: 0.00211 AC: 48 AN: 22782

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

African (AFR) AF: 0.0270 AC: 1111 AN: 41110

American (AMR) AF: 0.00341 AC: 52 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67652

Other (OTH) AF: 0.00617 AC: 13 AN: 2106

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

Mar 17, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.5
DANN	Benign	0.64
PhyloP100		-0.079
PromoterAI		0.014	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs534068817; hg19: chr5-179247766;