Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003900.5(SQSTM1):c.712A>G(p.Lys238Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0034 in 1,614,012 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 24 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.06

Publications

29 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01183033).

BP6

Variant 5-179825184-A-G is Benign according to our data. Variant chr5-179825184-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00241 (367/152314) while in subpopulation SAS AF = 0.00394 (19/4828). AF 95% confidence interval is 0.00309. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SQSTM1	NM_003900.5	MANE Select	c.712A>G	p.Lys238Glu	missense	Exon 5 of 8	NP_003891.1
SQSTM1	NM_001142298.2		c.460A>G	p.Lys154Glu	missense	Exon 6 of 9	NP_001135770.1
SQSTM1	NM_001142299.2		c.460A>G	p.Lys154Glu	missense	Exon 6 of 9	NP_001135771.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.712A>G	p.Lys238Glu	missense	Exon 5 of 8	ENSP00000374455.4
SQSTM1	ENST00000360718.5	TSL:1	c.460A>G	p.Lys154Glu	missense	Exon 4 of 7	ENSP00000353944.5
SQSTM1	ENST00000510187.5	TSL:5	c.712A>G	p.Lys238Glu	missense	Exon 5 of 7	ENSP00000424477.1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00282

AC:

708

AN:

251416

AF XY:

0.00322

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00363

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00351

AC:

5126

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

2599

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33478

American (AMR)

AF:

0.00273

AC:

122

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00492

AC:

424

AN:

86254

European-Finnish (FIN)

AF:

0.000544

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00390

AC:

4341

AN:

1111924

Other (OTH)

AF:

0.00293

AC:

177

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

288

576

863

1151

1439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00241

AC:

367

AN:

152314

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41574

American (AMR)

AF:

0.00373

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00394

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00346

AC:

235

AN:

68016

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00320

Hom.:

Bravo

AF:

0.00270

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00241

AC:

293

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00362

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

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

Paget disease of bone 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.012

MetaSVM

Uncertain

-0.040

MutationAssessor

Uncertain

2.5

PhyloP100

4.1

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.010

Polyphen

0.72

Vest4

0.67

MVP

0.94

MPC

0.45

ClinPred

0.018

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.69

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over