Variant rs774355338 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003900.5(SQSTM1):c.185G>T(p.Gly62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000945 in 1,375,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000096 ( 1 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:2

Conservation

PhyloP100: 1.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045209467).

BP6

Variant 5-179821121-G-T is Benign according to our data. Variant chr5-179821121-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586684.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SQSTM1	NM_003900.5 linkuse as main transcript	c.185G>T	p.Gly62Val	missense_variant	1/8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2 linkuse as main transcript	c.-47-1837G>T		intron_variant			NP_001135770.1
SQSTM1	NM_001142299.2 linkuse as main transcript	c.-47-1837G>T		intron_variant			NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.185G>T	p.Gly62Val	missense_variant	1/8	1	NM_003900.5	ENSP00000374455	P1	Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000518

AC:

AN:

19306

Hom.:

AF XY:

0.000733

AC XY:

AN XY:

12280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000965

AC:

118

AN:

1222918

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

593636

show subpopulations

Gnomad4 AFR exome

AF:

0.0000409

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00204

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000200

Gnomad4 OTH exome

AF:

0.0000397

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T;T;T

Eigen

Benign

-0.013

Eigen_PC

Benign

0.0070

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.80

T;.;T;.

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.045

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Benign

0.21

Sift

Benign

0.063

T;.;T;T

Sift4G

Benign

0.38

T;D;T;T

Polyphen

0.87

P;.;.;D

Vest4

0.54

MutPred

0.51

Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);

MVP

0.86

MPC

0.56

ClinPred

0.20

GERP RS

2.5

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.4

Varity_R

0.31

gMVP

0.36

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

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