rs140226523

Variant names:

• chr5-179833238-C-T
• rs140226523
• NM_003900.5:c.961C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003900.5(SQSTM1):​c.961C>T​(p.Arg321Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00184 in 1,580,682 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0086 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.34
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003144294).
• BP6: Variant 5-179833238-C-T is Benign according to our data. Variant chr5-179833238-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0086 (1309/152278) while in subpopulation AFR AF = 0.0271 (1126/41548). AF 95% confidence interval is 0.0258. There are 14 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

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.961C>T	p.Arg321Cys	missense	Exon 6 of 8	NP_003891.1	Q13501-1
	SQSTM1	NM_001142298.2		c.709C>T	p.Arg237Cys	missense	Exon 7 of 9	NP_001135770.1	Q13501-2
	SQSTM1	NM_001142299.2		c.709C>T	p.Arg237Cys	missense	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.961C>T	p.Arg321Cys	missense	Exon 6 of 8	ENSP00000374455.4	Q13501-1
	SQSTM1	ENST00000360718.5	TSL:1	c.709C>T	p.Arg237Cys	missense	Exon 5 of 7	ENSP00000353944.5	Q13501-2
	SQSTM1	ENST00000884700.1		c.985C>T	p.Arg329Cys	missense	Exon 6 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes AF: 0.00859 AC: 1307 AN: 152160 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00279 AC: 525 AN: 188286 AF XY: 0.00232

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000736

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000650

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00111 AC: 1592 AN: 1428404 Hom.: 15 Cov.: 36 AF XY: 0.00100 AC XY: 710 AN XY: 708468

African (AFR) AF: 0.0277 AC: 909 AN: 32780

American (AMR) AF: 0.00386 AC: 153 AN: 39670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 37826

South Asian (SAS) AF: 0.0000840 AC: 7 AN: 83362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46262

Middle Eastern (MID) AF: 0.00228 AC: 11 AN: 4834

European-Non Finnish (NFE) AF: 0.000342 AC: 376 AN: 1098884

Other (OTH) AF: 0.00230 AC: 136 AN: 59180

GnomAD4 genome AF: 0.00860 AC: 1309 AN: 152278 Hom.: 14 Cov.: 33 AF XY: 0.00862 AC XY: 642 AN XY: 74452

African (AFR) AF: 0.0271 AC: 1126 AN: 41548

American (AMR) AF: 0.00882 AC: 135 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.000441 AC: 30 AN: 68020

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00344 Hom.: 3

Bravo AF: 0.00937

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0317 AC: 139

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.00267 AC: 320

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (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)
-	-	1	SQSTM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.26
Sift	Benign	0.038	D
Sift4G	Uncertain	0.053	T
Polyphen		0.21	B
Vest4		0.28
MVP		0.92
MPC		0.27
ClinPred		0.017	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.098
gMVP		0.14
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs140226523; hg19: chr5-179260238; COSMIC: COSV107350610; COSMIC: COSV107350610;