rs61748794

Positions:

chr5-179833232-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003900.5(SQSTM1):c.955G>A(p.Glu319Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,588,600 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 48 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 38 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.390

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 links:

SQSTM1 (HGNC:):

SQSTM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021701753).

BP6

Variant 5-179833232-G-A is Benign according to our data. Variant chr5-179833232-G-A is described in ClinVar as [Benign]. Clinvar id is 353165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179833232-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1985/152286) while in subpopulation AFR AF= 0.0454 (1886/41560). AF 95% confidence interval is 0.0437. There are 48 homozygotes in gnomad4. There are 929 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1985 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5 linkuse as main transcript	c.955G>A	p.Glu319Lys	missense_variant	6/8	ENST00000389805.9	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.703G>A	p.Glu235Lys	missense_variant	7/9		NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2 linkuse as main transcript	c.703G>A	p.Glu235Lys	missense_variant	7/9		NP_001135771.1	Q13501-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.955G>A	p.Glu319Lys	missense_variant	6/8	1	NM_003900.5	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.703G>A	p.Glu235Lys	missense_variant	5/7	1		ENSP00000353944.5	Q13501-2
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.950+5G>A		splice_region_variant, intron_variant		5		ENSP00000424477.1	E7EMC7
SQSTM1	ENST00000466342.1 linkuse as main transcript	n.654G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1982

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00439

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:

0.000206

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00353

AC:

716

AN:

202832

Hom.:

AF XY:

0.00262

AC XY:

291

AN XY:

110868

show subpopulations

Gnomad AFR exome

AF:

0.0525

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000361

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.000952

GnomAD4 exome

AF:

0.00134

AC:

1928

AN:

1436314

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

837

AN XY:

712938

show subpopulations

Gnomad4 AFR exome

AF:

0.0467

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.0000476

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000862

Gnomad4 OTH exome

AF:

0.00259

GnomAD4 genome

AF:

0.0130

AC:

1985

AN:

152286

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

929

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0454

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00447

Hom.:

Bravo

AF:

0.0143

ESP6500AA

AF:

0.0408

AC:

179

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00393

AC:

473

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2020	This variant is associated with the following publications: (PMID: 22972638) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SQSTM1: BP4, BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 25, 2024

- -

Paget disease of bone 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.8

DANN

Benign

0.82

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.14

Sift

Benign

0.92

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.0070

B;.

Vest4

0.10

MVP

0.78

MPC

0.15

ClinPred

0.0011

GERP RS

-0.72

Varity_R

0.032

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over