chr5-179833238-C-T

Position:

chr5-179833238-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000389805.9(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
ENST00000389805.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.34

Variant links:

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 links:

SQSTM1 (HGNC:):

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SQSTM1	NM_003900.5 linkuse as main transcript	c.961C>T	p.Arg321Cys	missense_variant	6/8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	7/9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	7/9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.961C>T	p.Arg321Cys	missense_variant	6/8	1	NM_003900.5	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.709C>T	p.Arg237Cys	missense_variant	5/7	1		ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.950+11C>T		intron_variant		5		ENSP00000424477.1	E7EMC7
SQSTM1	ENST00000466342.1 linkuse as main transcript	n.660C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.00859

AC:

1307

AN:

152160

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00232

AC XY:

239

AN XY:

102954

show subpopulations

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.:

Cov.:

AF XY:

0.00100

AC XY:

710

AN XY:

708468

show subpopulations

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.:

Cov.:

AF XY:

0.00862

AC XY:

642

AN XY:

74452

show subpopulations

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.:

Bravo

AF:

0.00937

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0317

AC:

139

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.00267

AC:

320

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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) -

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, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.20

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over