5-179820939-G-A

Variant names:

• chr5-179820939-G-A
• rs1309887153
• NM_003900.5:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003900.5(SQSTM1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SQSTM1 NM_003900.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26
• Publications: 0 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000301422 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 85 codons. Genomic position: 179823005. Lost 0.191 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.-47-2019G>A		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2019G>A		intron_variant	Intron 2 of 8		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.3G>A	p.Met1?	start_lost	Exon 1 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000536 AC: 1 AN: 186704 AF XY: 0.00000947

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398624 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693114

African (AFR) AF: 0.00 AC: 0 AN: 29042

American (AMR) AF: 0.00 AC: 0 AN: 40090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24676

East Asian (EAS) AF: 0.00 AC: 0 AN: 34242

South Asian (SAS) AF: 0.00 AC: 0 AN: 81414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086076

Other (OTH) AF: 0.00 AC: 0 AN: 57950

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

May 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of the initiator codon has been observed in individual(s) with autosomal recessive neurodegeneration with ataxia, dystonia, and gaze palsy (PMID: 27545679). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the SQSTM1 mRNA. The next in-frame methionine is located at codon 85. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T;T;T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;D;.
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.21	T
PhyloP100		3.3
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.27	B;.;.;B
Vest4		0.80
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0109);Gain of catalytic residue at M1 (P = 0.0109);Gain of catalytic residue at M1 (P = 0.0109);Gain of catalytic residue at M1 (P = 0.0109);
MVP		0.93
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.50
Mutation Taster		=10/190	disease causing

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

Other links and lift over

dbSNP: rs1309887153; hg19: chr5-179247939;