rs776749939

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3_ModeratePP5BS2

The NM_003900.5(SQSTM1):c.1160C>T(p.Pro387Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P387A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 1 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003900.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

PP5

Variant 5-179833777-C-T is Pathogenic according to our data. Variant chr5-179833777-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202211.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr5-179833777-C-T is described in UniProt as null. Variant chr5-179833777-C-T is described in UniProt as null. Variant chr5-179833777-C-T is described in UniProt as null. Variant chr5-179833777-C-T is described in UniProt as null.

BS2

High AC in GnomAdExome at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SQSTM1	NM_003900.5 linkuse as main transcript	c.1160C>T	p.Pro387Leu	missense_variant	7/8	ENST00000389805.9
SQSTM1	NM_001142298.2 linkuse as main transcript	c.908C>T	p.Pro303Leu	missense_variant	8/9
SQSTM1	NM_001142299.2 linkuse as main transcript	c.908C>T	p.Pro303Leu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.1160C>T	p.Pro387Leu	missense_variant	7/8	1	NM_003900.5	P1	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.908C>T	p.Pro303Leu	missense_variant	6/7	1			Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.950+550C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251090

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2014

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2018

The P387L variant in the SQSTM1 gene has been reported in individuals with Paget disease of bone as well as inindividuals with frontotemporal dementia (Johnson-Pais et al., 2003; Gennari et al., 2010; Le Ber et al., 2013; vander Zee et al., 2014). In vitro studies demonstrate that the P387L results in decreased binding of monoubiquitin andpolyubiquitin as compared to wild-type (Cavey et al., 2006). The P387L variant was not observed in approximately6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating itis not a common benign variant in these populations. The P387L variant is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties and occurs at aposition that is conserved across species. The P387L variant is a strong candidate for a pathogenic variant, howeverthe possibility it may be a rare benign variant cannot be excluded. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 387 of the SQSTM1 protein (p.Pro387Leu). This variant is present in population databases (rs776749939, gnomAD 0.03%). This missense change has been observed in individual(s) with Paget disease, frontotemporal dementia or dementia (PMID: 14584883, 20200946, 22972638, 24042580, 24899140, 25796131, 29525180). ClinVar contains an entry for this variant (Variation ID: 202211). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SQSTM1 protein function. Experimental studies have shown that this missense change affects SQSTM1 function (PMID: 16691492, 17229008). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.9

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.87

P;.

Vest4

0.77

MVP

0.99

MPC

0.26

ClinPred

0.25

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.63

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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