5-179813910-A-C

Variant names:

• chr5-179813910-A-C
• rs10516140
• NM_001142298.2:c.-48+2228A>C

Variant summary

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

The NM_001142298.2(SQSTM1):​c.-48+2228A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 152,110 control chromosomes in the GnomAD database, including 45,229 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 0.76 (45229 hom., cov: 32)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-48+2228A>C		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-48+2228A>C		intron_variant	Intron 2 of 8		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000514093.5	c.-48+2228A>C		intron_variant	Intron 2 of 5	5		ENSP00000427308.1
ENSG00000301422	ENST00000778815.1	n.176-1017T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115872 AN: 151992 Hom.: 45195 Cov.: 32

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.732

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.782

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

GnomAD4 genome AF: 0.762 AC: 115958 AN: 152110 Hom.: 45229 Cov.: 32 AF XY: 0.766 AC XY: 56968 AN XY: 74362

African (AFR) AF: 0.580 AC: 24031 AN: 41432

American (AMR) AF: 0.805 AC: 12296 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2733 AN: 3472

East Asian (EAS) AF: 0.732 AC: 3784 AN: 5172

South Asian (SAS) AF: 0.829 AC: 4004 AN: 4828

European-Finnish (FIN) AF: 0.864 AC: 9153 AN: 10592

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57417 AN: 68010

Other (OTH) AF: 0.784 AC: 1658 AN: 2114

Alfa AF: 0.807 Hom.: 124013

Bravo AF: 0.747

Asia WGS AF: 0.777 AC: 2703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.1
DANN	Benign	0.66
PhyloP100		-0.0050
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10516140; hg19: chr5-179240910; COSMIC: COSV65364126;