5-179833231-C-A

Variant names:

• chr5-179833231-C-A
• rs56092424
• NM_003900.5:c.954C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003900.5(SQSTM1):​c.954C>A​(p.Ser318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S318S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.75
• Publications: 9 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-5.75 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.954C>A	p.Ser318Ser	synonymous_variant	Exon 6 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.702C>A	p.Ser234Ser	synonymous_variant	Exon 7 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.702C>A	p.Ser234Ser	synonymous_variant	Exon 7 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.954C>A	p.Ser318Ser	synonymous_variant	Exon 6 of 8	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.702C>A	p.Ser234Ser	synonymous_variant	Exon 5 of 7	1		ENSP00000353944.5
SQSTM1	ENST00000466342.1	n.653C>A		non_coding_transcript_exon_variant	Exon 4 of 4	2
SQSTM1	ENST00000510187.5	c.950+4C>A		splice_region_variant, intron_variant	Intron 6 of 6	5		ENSP00000424477.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000493 AC: 1 AN: 202768 AF XY: 0.00000902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000681

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436430 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 712920

African (AFR) AF: 0.00 AC: 0 AN: 32966

American (AMR) AF: 0.00 AC: 0 AN: 40728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 38286

South Asian (SAS) AF: 0.00 AC: 0 AN: 84098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5086

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102126

Other (OTH) AF: 0.00 AC: 0 AN: 59412

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.024
DANN	Benign	0.84
PhyloP100		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs56092424; hg19: chr5-179260231;