5-179826926-A-G

Variant names:

• chr5-179826926-A-G
• rs565280
• NM_003900.5:c.754+1700A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003900.5(SQSTM1):​c.754+1700A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 151,974 control chromosomes in the GnomAD database, including 33,043 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.65 (33043 hom., cov: 31)
• Consequence: SQSTM1 NM_003900.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.254
• Publications: 21 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.754+1700A>G		intron_variant	Intron 5 of 7	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.502+1700A>G		intron_variant	Intron 6 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.502+1700A>G		intron_variant	Intron 6 of 8		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.754+1700A>G		intron_variant	Intron 5 of 7	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.502+1700A>G		intron_variant	Intron 4 of 6	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.754+1700A>G		intron_variant	Intron 5 of 6	5		ENSP00000424477.1
SQSTM1	ENST00000466342.1	n.453+1700A>G		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98317 AN: 151856 Hom.: 32988 Cov.: 31

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.618

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.648 AC: 98430 AN: 151974 Hom.: 33043 Cov.: 31 AF XY: 0.652 AC XY: 48420 AN XY: 74264

African (AFR) AF: 0.812 AC: 33654 AN: 41458

American (AMR) AF: 0.713 AC: 10885 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3468

East Asian (EAS) AF: 0.789 AC: 4081 AN: 5174

South Asian (SAS) AF: 0.625 AC: 3011 AN: 4820

European-Finnish (FIN) AF: 0.604 AC: 6364 AN: 10534

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.534 AC: 36255 AN: 67942

Other (OTH) AF: 0.621 AC: 1311 AN: 2110

Alfa AF: 0.576 Hom.: 13754

Bravo AF: 0.663

Asia WGS AF: 0.728 AC: 2533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.5
DANN	Benign	0.62
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs565280; hg19: chr5-179253926;