5-179836435-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_Strong

The NM_003900.5(SQSTM1):c.1166-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SQSTM1
NM_003900.5 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96

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:

MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

MRNIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of 2, new splice context is: tccttactgtttcggcaaAGgct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
SQSTM1	NM_003900.5 linkuse as main transcript	c.1166-1G>A	splice_acceptor_variant	ENST00000389805.9
SQSTM1	NM_001142298.2 linkuse as main transcript	c.914-1G>A	splice_acceptor_variant
SQSTM1	NM_001142299.2 linkuse as main transcript	c.914-1G>A	splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9 linkuse as main transcript	c.1166-1G>A	splice_acceptor_variant		1	NM_003900.5	P1	Q13501-1
SQSTM1	ENST00000360718.5 linkuse as main transcript	c.914-1G>A	splice_acceptor_variant		1			Q13501-2
MRNIP	ENST00000522663.5 linkuse as main transcript	c.*1255C>T	3_prime_UTR_variant, NMD_transcript_variant	9/9	1
SQSTM1	ENST00000510187.5 linkuse as main transcript	c.951-36G>A	intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250978

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2019

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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with SQSTM1-related conditions. This variant is present in population databases (rs529512338, ExAC 0.01%). This sequence change affects an acceptor splice site in the last intron (intron 7) of the SQSTM1 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.35

Position offset: 3

DS_AL_spliceai

0.92

Position offset: 1

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