chr5-179820941-C-T

Position:

chr5-179820941-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_003900.5(SQSTM1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,551,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.704

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 Likely_benign. Variant got -3 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity SQSTM_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.2698727).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SQSTM1	NM_003900.5 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/8	ENST00000389805.9
SQSTM1	NM_001142298.2 linkuse as main transcript	c.-47-2017C>T		intron_variant
SQSTM1	NM_001142299.2 linkuse as main transcript	c.-47-2017C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/8	1	NM_003900.5	P1	Q13501-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000268

AC:

AN:

186484

Hom.:

AF XY:

0.0000190

AC XY:

AN XY:

105468

show subpopulations

Gnomad AFR exome

AF:

0.000244

Gnomad AMR exome

AF:

0.0000691

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000272

AC:

AN:

1398812

Hom.:

Cov.:

AF XY:

0.0000231

AC XY:

AN XY:

693446

show subpopulations

Gnomad4 AFR exome

AF:

0.000689

Gnomad4 AMR exome

AF:

0.0000500

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000292

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000552

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000138

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000482

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2021

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the SQSTM1 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the SQSTM1 protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SQSTM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 861123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.057

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.84

T;.;T;.

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.6

L;.;.;.

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.72

N;.;N;N

REVEL

Benign

0.044

Sift

Uncertain

0.011

D;.;D;D

Sift4G

Uncertain

0.035

D;D;D;D

Polyphen

0.33

B;.;.;P

Vest4

0.36

MVP

0.94

MPC

0.29

ClinPred

0.40

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.10

gMVP

0.42

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