rs140226523

Positions:

• chr5-179833238-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:5
• Conservation: PhyloP100: 4.34

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 259193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833238-C-T is described in UniProt as null. Variant chr5-179833238-C-T is described in UniProt as null. Variant chr5-179833238-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.961C>T	p.Arg321Cys	missense_variant	6/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.709C>T	p.Arg237Cys	missense_variant	7/9
SQSTM1	NM_001142299.2	c.709C>T	p.Arg237Cys	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.961C>T	p.Arg321Cys	missense_variant	6/8	1	NM_003900.5	P1
SQSTM1	ENST00000360718.5	c.709C>T	p.Arg237Cys	missense_variant	5/7	1
SQSTM1	ENST00000510187.5	c.950+11C>T		intron_variant		5
SQSTM1	ENST00000466342.1	n.660C>T		non_coding_transcript_exon_variant	4/4	2

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

GnomAD3 exomes AF: 0.00279 AC: 525 AN: 188286 Hom.: 11 AF XY: 0.00232 AC XY: 239 AN XY: 102954

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 SAS exome AF: 0.000113

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

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.00386

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000840

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000342

Gnomad4 OTH exome AF: 0.00230

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

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00303 Hom.: 1

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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2020	This variant is associated with the following publications: (PMID: 32036052, 31859009, 31434890, 24899140, 22084127) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2018	- -

Paget disease of bone 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

SQSTM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.26
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.053	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs140226523; hg19: chr5-179260238;