5-179820612-C-T

Variant names:

• chr5-179820612-C-T
• rs116436326
• ENST00000464493.5:n.6C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000464493.5(SQSTM1):​n.6C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00786 in 284,442 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: SQSTM1 ENST00000464493.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.424
• 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=-0.63).
• BP6: Variant 5-179820612-C-T is Benign according to our data. Variant chr5-179820612-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1220135.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1975/152350) while in subpopulation AFR AF = 0.0458 (1905/41578). AF 95% confidence interval is 0.0441. There are 35 homozygotes in GnomAd4. There are 970 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-47-2346C>T		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2346C>T		intron_variant	Intron 2 of 8		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000464493.5	n.6C>T		non_coding_transcript_exon_variant	Exon 1 of 4	4
SQSTM1	ENST00000514093.5	c.-47-2346C>T		intron_variant	Intron 2 of 5	5		ENSP00000427308.1
SQSTM1	ENST00000422245.5	c.-48+1575C>T		intron_variant	Intron 1 of 3	4		ENSP00000394534.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1973 AN: 152232 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.00197 AC: 260 AN: 132092 Hom.: 3 Cov.: 0 AF XY: 0.00148 AC XY: 99 AN XY: 67058

African (AFR) AF: 0.0484 AC: 200 AN: 4134

American (AMR) AF: 0.00182 AC: 6 AN: 3294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5260

East Asian (EAS) AF: 0.00 AC: 0 AN: 10796

South Asian (SAS) AF: 0.00 AC: 0 AN: 4962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9772

Middle Eastern (MID) AF: 0.00142 AC: 1 AN: 706

European-Non Finnish (NFE) AF: 0.000155 AC: 13 AN: 84110

Other (OTH) AF: 0.00442 AC: 40 AN: 9058

GnomAD4 genome AF: 0.0130 AC: 1975 AN: 152350 Hom.: 35 Cov.: 33 AF XY: 0.0130 AC XY: 970 AN XY: 74502

African (AFR) AF: 0.0458 AC: 1905 AN: 41578

American (AMR) AF: 0.00307 AC: 47 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.0143 Hom.: 5

Bravo AF: 0.0151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 29, 2018

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	-0.63
CADD	Benign	3.3
DANN	Benign	0.61
PhyloP100		-0.42
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs116436326; hg19: chr5-179247612;