dbSNP rs4935: SQSTM1:p.Asp292Asp (chr5-179833153-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003900.5(SQSTM1):c.876C>T(p.Asp292Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,613,700 control chromosomes in the GnomAD database, including 262,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 30584 hom., cov: 33)

Exomes 𝑓: 0.56 ( 232252 hom. )

Consequence

SQSTM1
NM_003900.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.38

Publications

50 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: Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
frontotemporal dementia and/or amyotrophic lateral sclerosis 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
osteosarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Paget disease of bone 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 5-179833153-C-T is Benign according to our data. Variant chr5-179833153-C-T is described in ClinVar as Benign. ClinVar VariationId is 259189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

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	UniProt
SQSTM1	NM_003900.5	MANE Select	c.876C>T	p.Asp292Asp	synonymous	Exon 6 of 8	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2		c.624C>T	p.Asp208Asp	synonymous	Exon 7 of 9	NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2		c.624C>T	p.Asp208Asp	synonymous	Exon 7 of 9	NP_001135771.1	Q13501-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.876C>T	p.Asp292Asp	synonymous	Exon 6 of 8	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5	TSL:1	c.624C>T	p.Asp208Asp	synonymous	Exon 5 of 7	ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000884700.1		c.900C>T	p.Asp300Asp	synonymous	Exon 6 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

95039

AN:

151954

Hom.:

30556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.729

Gnomad AMI

AF:

0.663

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.640

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.652

Gnomad FIN

AF:

0.620

Gnomad MID

AF:

0.598

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.606

GnomAD2 exomes

AF:

0.628

AC:

157513

AN:

250744

AF XY:

0.617

show subpopulations

Gnomad AFR exome

AF:

0.732

Gnomad AMR exome

AF:

0.791

Gnomad ASJ exome

AF:

0.644

Gnomad EAS exome

AF:

0.848

Gnomad FIN exome

AF:

0.618

Gnomad NFE exome

AF:

0.528

Gnomad OTH exome

AF:

0.608

GnomAD4 exome

AF:

0.558

AC:

814997

AN:

1461628

Hom.:

232252

Cov.:

AF XY:

0.559

AC XY:

406325

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.736

AC:

24632

AN:

33478

American (AMR)

AF:

0.778

AC:

34808

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.635

AC:

16594

AN:

26132

East Asian (EAS)

AF:

0.861

AC:

34166

AN:

39694

South Asian (SAS)

AF:

0.630

AC:

54358

AN:

86246

European-Finnish (FIN)

AF:

0.615

AC:

32819

AN:

53378

Middle Eastern (MID)

AF:

0.612

AC:

3528

AN:

5764

European-Non Finnish (NFE)

AF:

0.521

AC:

578956

AN:

1111844

Other (OTH)

AF:

0.582

AC:

35136

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

22405

44809

67214

89618

112023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16836

33672

50508

67344

84180

<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:

0.625

AC:

95120

AN:

152072

Hom.:

30584

Cov.:

AF XY:

0.632

AC XY:

46994

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.728

AC:

30215

AN:

41482

American (AMR)

AF:

0.695

AC:

10629

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.640

AC:

2221

AN:

3472

East Asian (EAS)

AF:

0.848

AC:

4384

AN:

5170

South Asian (SAS)

AF:

0.651

AC:

3132

AN:

4812

European-Finnish (FIN)

AF:

0.620

AC:

6549

AN:

10568

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.529

AC:

35920

AN:

67964

Other (OTH)

AF:

0.608

AC:

1285

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1795

3590

5386

7181

8976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<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:

0.562

Hom.:

37957

Bravo

AF:

0.636

Asia WGS

AF:

0.762

AC:

2651

AN:

3478

EpiCase

AF:

0.528

EpiControl

AF:

0.530

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Paget disease of bone 2, early-onset (3)

not provided (2)

Paget disease of bone 3 (2)

Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (1)

Myopathy, distal, with rimmed vacuoles (1)

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.27

(source)

DANN

Benign

0.82

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over