NM_001142298.2:c.-47-2160G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001142298.2(SQSTM1):​c.-47-2160G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 822,616 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (17 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (9 hom.)
• Consequence: SQSTM1 NM_001142298.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-179820798-G-C is Benign according to our data. Variant chr5-179820798-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1214418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0088 (1340/152276) while in subpopulation AFR AF = 0.0296 (1230/41568). AF 95% confidence interval is 0.0282. There are 17 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_001142298.2	c.-47-2160G>C		intron_variant	Intron 2 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.-47-2160G>C		intron_variant	Intron 2 of 8		NP_001135771.1
SQSTM1	NM_003900.5	c.-139G>C		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>C		upstream_gene_variant		1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1337 AN: 152158 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00862

GnomAD4 exome AF: 0.00161 AC: 1082 AN: 670340 Hom.: 9 Cov.: 9 AF XY: 0.00154 AC XY: 517 AN XY: 336476

African (AFR) AF: 0.0307 AC: 409 AN: 13316

American (AMR) AF: 0.00324 AC: 29 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: 0.0000505 AC: 2 AN: 39630

European-Finnish (FIN) AF: 0.0000687 AC: 2 AN: 29098

Middle Eastern (MID) AF: 0.000881 AC: 2 AN: 2270

European-Non Finnish (NFE) AF: 0.00105 AC: 531 AN: 507716

Other (OTH) AF: 0.00337 AC: 107 AN: 31722

GnomAD4 genome AF: 0.00880 AC: 1340 AN: 152276 Hom.: 17 Cov.: 34 AF XY: 0.00823 AC XY: 613 AN XY: 74472

African (AFR) AF: 0.0296 AC: 1230 AN: 41568

American (AMR) AF: 0.00268 AC: 41 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 67988

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00825 Hom.: 3

Bravo AF: 0.0101

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.0
DANN	Benign	0.52
PhyloP100		-0.017
PromoterAI		-0.18	Neutral
Mutation Taster		=100/0	polymorphism

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;