rs576610830

Variant names:

• chr5-179820798-G-A
• rs576610830
• NM_001142298.2:c.-47-2160G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-179820798-G-A
• chr5-179820798-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142298.2(SQSTM1):​c.-47-2160G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 670,356 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0170
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-47-2160G>A		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2160G>A		intron_variant	Intron 2 of 8		NP_001135771.1
SQSTM1	NM_003900.5	c.-139G>A		upstream_gene_variant		ENST00000389805.9	NP_003891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.-139G>A		upstream_gene_variant		1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000298 AC: 2 AN: 670356 Hom.: 0 Cov.: 9 AF XY: 0.00000594 AC XY: 2 AN XY: 336484

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13328

American (AMR) AF: 0.00 AC: 0 AN: 8950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13116

East Asian (EAS) AF: 0.00 AC: 0 AN: 24522

South Asian (SAS) AF: 0.00 AC: 0 AN: 39630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2270

European-Non Finnish (NFE) AF: 0.00000394 AC: 2 AN: 507720

Other (OTH) AF: 0.00 AC: 0 AN: 31722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.6
DANN	Benign	0.82
PhyloP100		-0.017
PromoterAI		-0.0036	Neutral

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: rs576610830; hg19: chr5-179247798;