chr5-179821034-C-T

Position:

chr5-179821034-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003900.5(SQSTM1):c.98C>T(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,554,964 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:2

Conservation

PhyloP100: 2.76

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010404259).

BS2

High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.-47-1924C>T		intron_variant			NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 linkuse as main transcript	c.-47-1924C>T		intron_variant			NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/8	1	NM_003900.5	ENSP00000374455.4		Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000813

AC:

137

AN:

168614

Hom.:

AF XY:

0.000845

AC XY:

AN XY:

95892

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.000850

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000709

GnomAD4 exome

AF:

0.00115

AC:

1617

AN:

1402658

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

791

AN XY:

696570

show subpopulations

Gnomad4 AFR exome

AF:

0.000205

Gnomad4 AMR exome

AF:

0.000772

Gnomad4 ASJ exome

AF:

0.0000808

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000247

Gnomad4 FIN exome

AF:

0.00151

Gnomad4 NFE exome

AF:

0.00131

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000735

AC:

112

AN:

152306

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000812

AC:

ExAC

AF:

0.000679

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:2

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

Nov 01, 2013

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 27, 2023

Variant summary: SQSTM1 c.98C>T (p.Ala33Val) results in a non-conservative amino acid change located in the PB1 domain (IPR000270) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00081 in 168614 control chromosomes (gnomAD). c.98C>T has been reported in the literature in individuals affected with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, some of whom had a positive family history of similar disorders, but with no segregation data available (e.g. Fecto_2011, Le Ber_2013, van der Zee_2014, Borghero_2016, Goldstein_2019, McCann_2020, Mol_2021). Additionally, the variant has also been reported in controls (e.g. van der Zee_2014, Mol_2021) and in at least one case, the affected individual also harbored a potentially pathogenic variant in a different gene (e.g. Borghero_2016). Therefore, these reports do not provide unequivocal conclusions about association of the variant with SQSTM1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27156075, 22084127, 31108397, 24042580, 32409511, 32843152, 24899140). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Paget disease of bone 3

Uncertain:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2021

Unlikely to be causative of SQSTM1-related frontotemporal dementia/amyotrophic lateral sclerosis (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2021

This variant is associated with the following publications: (PMID: 31108397, 26836416, 24138988, 24486447, 25796131, 25382069, 23447461, 27275741, 27156075, 22084127, 24042580, 24899140) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;T;T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.74

T;.;D;.

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.69

N;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.040

N;.;N;N

REVEL

Benign

0.049

Sift

Benign

0.42

T;.;T;T

Sift4G

Benign

0.54

T;D;T;T

Polyphen

0.0080

B;.;.;B

Vest4

0.30

MVP

0.88

MPC

0.13

ClinPred

0.028

GERP RS

0.80

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.078

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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