5-179833231-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003900.5(SQSTM1):​c.954C>T​(p.Ser318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,588,584 control chromosomes in the GnomAD database, including 632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (179 hom., cov: 33)
  • Exomes 𝑓: 0.022 (453 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

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

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-179833231-C-T is Benign according to our data. Variant chr5-179833231-C-T is described in ClinVar as Benign. ClinVar VariationId is 259192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	NM_003900.5	MANE Select	c.954C>T	p.Ser318Ser	synonymous	Exon 6 of 8	NP_003891.1	Q13501-1
	SQSTM1	NM_001142298.2		c.702C>T	p.Ser234Ser	synonymous	Exon 7 of 9	NP_001135770.1	Q13501-2
	SQSTM1	NM_001142299.2		c.702C>T	p.Ser234Ser	synonymous	Exon 7 of 9	NP_001135771.1	Q13501-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.954C>T	p.Ser318Ser	synonymous	Exon 6 of 8	ENSP00000374455.4	Q13501-1
	SQSTM1	ENST00000360718.5	TSL:1	c.702C>T	p.Ser234Ser	synonymous	Exon 5 of 7	ENSP00000353944.5	Q13501-2
	SQSTM1	ENST00000884700.1		c.978C>T	p.Ser326Ser	synonymous	Exon 6 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5453 AN: 152118 Hom.: 177 Cov.: 33

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0212 AC: 4300 AN: 202768 AF XY: 0.0205

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.000341

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0217 AC: 31140 AN: 1436348 Hom.: 453 Cov.: 36 AF XY: 0.0213 AC XY: 15207 AN XY: 712876

African (AFR) AF: 0.0749 AC: 2469 AN: 32948

American (AMR) AF: 0.0134 AC: 546 AN: 40726

Ashkenazi Jewish (ASJ) AF: 0.0500 AC: 1288 AN: 25738

East Asian (EAS) AF: 0.000287 AC: 11 AN: 38288

South Asian (SAS) AF: 0.0140 AC: 1181 AN: 84096

European-Finnish (FIN) AF: 0.0171 AC: 822 AN: 47986

Middle Eastern (MID) AF: 0.0380 AC: 193 AN: 5084

European-Non Finnish (NFE) AF: 0.0209 AC: 23074 AN: 1102074

Other (OTH) AF: 0.0262 AC: 1556 AN: 59408

GnomAD4 genome AF: 0.0359 AC: 5461 AN: 152236 Hom.: 179 Cov.: 33 AF XY: 0.0337 AC XY: 2511 AN XY: 74434

African (AFR) AF: 0.0751 AC: 3120 AN: 41522

American (AMR) AF: 0.0241 AC: 369 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0432 AC: 150 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4824

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1435 AN: 68020

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0277 Hom.: 20

Bravo AF: 0.0388

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Paget disease of bone 2, early-onset (1)
-	-	1	Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)
-	-	1	Paget disease of bone 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.18
DANN	Benign	0.88
PhyloP100		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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; COSMIC: COSV52975051;