Genetic Variant SQSTM1:p.Met1? (chr5-179820939-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_003900.5(SQSTM1):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SQSTM1
NM_003900.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.26

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5 link	c.3G>T	p.Met1?	start_lost	Exon 1 of 8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 link	c.-47-2019G>T		intron_variant	Intron 2 of 8		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 link	c.-47-2019G>T		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.3G>T	p.Met1?	start_lost	Exon 1 of 8	1	NM_003900.5	ENSP00000374455.4		Q13501-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1398624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693114

African (AFR)

AF:

0.00

AC:

AN:

29042

American (AMR)

AF:

0.00

AC:

AN:

40090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24676

East Asian (EAS)

AF:

0.00

AC:

AN:

34242

South Asian (SAS)

AF:

0.00

AC:

AN:

81414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086076

Other (OTH)

AF:

0.00

AC:

AN:

57950

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

T;T;T;T

Eigen

Benign

-0.039

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;.;D;.

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

-0.21

PhyloP100

3.3

PROVEAN

Benign

-1.5

N;.;N;N

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.27

B;.;.;B

Vest4

0.80

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.0109);Gain of catalytic residue at M1 (P = 0.0109);Gain of catalytic residue at M1 (P = 0.0109);Gain of catalytic residue at M1 (P = 0.0109);

MVP

0.93

ClinPred

0.99

GERP RS

4.6

PromoterAI

-0.34

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.97

gMVP

0.50

Mutation Taster

=10/190

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over