rs1302810798

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_003900.5(SQSTM1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,547,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SQSTM1
NM_003900.5 start_lost

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.16

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
osteosarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Paget disease of bone 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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

SQSTM1 links:

ENSG00000301422 (HGNC:):

ENSG00000301422 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 85 codons. Genomic position: 179823005. Lost 0.191 part of the original CDS.

PP5

Variant 5-179820937-A-G is Pathogenic according to our data. Variant chr5-179820937-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1019776.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.-47-2021A>G		intron_variant	Intron 2 of 8		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.-47-2021A>G		intron_variant	Intron 2 of 8		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	1	NM_003900.5	ENSP00000374455.4		Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000216

AC:

AN:

185012

AF XY:

0.0000286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000232

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.0000115

AC:

AN:

1395912

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

691524

show subpopulations

African (AFR)

AF:

0.0000691

AC:

AN:

28958

American (AMR)

AF:

0.0000251

AC:

AN:

39830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24606

East Asian (EAS)

AF:

0.0000587

AC:

AN:

34072

South Asian (SAS)

AF:

0.00

AC:

AN:

81170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5464

European-Non Finnish (NFE)

AF:

0.00000830

AC:

AN:

1084458

Other (OTH)

AF:

0.0000346

AC:

AN:

57818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000596

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

Pathogenic:1

Nov 24, 2020

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SQSTM1 c.1A>G (p.Met1?) variant disrupts the initiation codon and is predicted to interfere with normal protein expression. A different nucleotide change that also disrupts the initiation codon, c.2T>A, has been reported in a homozygous state in three siblings with childhood-onset neurodegeneration with ataxia, dystonia, gaze palsy and cognitive decline. Analysis of fibroblasts from affected individuals in this family, indicated the absence of any translated gene product (Haack et al. 2016). The c.1A>G variant is reported at a frequency of 0.000230 in the African/African-American population of the Genome Aggregation Database, which is based on two alleles in a region of good sequencing coverage. One additional allele affecting the initiation codon is also present in the Ashkenazi Jewish population. Based on the collective evidence, the c.1A>G variant is classified as likely pathogenic for childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. -

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

Uncertain:1

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the SQSTM1 mRNA. The next in-frame methionine is located at codon 85. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individual(s) with autosomal recessive neurodegeneration with ataxia, dystonia, and gaze palsy (PMID: 27545679). ClinVar contains an entry for this variant (Variation ID: 1019776). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided

Uncertain:1

Dec 13, 2021

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.35

T;T;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;.;D;.

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Benign

-0.30

PhyloP100

3.2

PROVEAN

Benign

-1.5

N;.;N;N

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.80

P;.;.;B

Vest4

0.80

MutPred

0.99

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.92

ClinPred

0.99

GERP RS

2.1

PromoterAI

-0.39

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.95

gMVP

0.53

Mutation Taster

=16/184

disease causing

(source)

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

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rs1302810798

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over