Genetic Variant SQSTM1:p.Pro273Pro (chr5-179833096-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003900.5(SQSTM1):c.819A>G(p.Pro273Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,614,220 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 3 hom. )

Consequence

SQSTM1
NM_003900.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.707

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: 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:

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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=-0.89).

BP6

Variant 5-179833096-A-G is Benign according to our data. Variant chr5-179833096-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.707 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000328 (50/152340) while in subpopulation EAS AF = 0.00928 (48/5172). AF 95% confidence interval is 0.00719. There are 2 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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	UniProt
SQSTM1	NM_003900.5	MANE Select	c.819A>G	p.Pro273Pro	synonymous	Exon 6 of 8	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2		c.567A>G	p.Pro189Pro	synonymous	Exon 7 of 9	NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2		c.567A>G	p.Pro189Pro	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.819A>G	p.Pro273Pro	synonymous	Exon 6 of 8	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5	TSL:1	c.567A>G	p.Pro189Pro	synonymous	Exon 5 of 7	ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000884700.1		c.843A>G	p.Pro281Pro	synonymous	Exon 6 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00926

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:

0.000803

AC:

202

AN:

251440

AF XY:

0.000802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00577

AC:

229

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112004

Other (OTH)

AF:

0.000149

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000328

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41588

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00928

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000279

Hom.:

Bravo

AF:

0.000434

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.21

(source)

DANN

Benign

0.42

PhyloP100

-0.71

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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