NM_003900.5:c.970-59T>C

Variant names:

• chr5-179833528-T-C
• rs155788
• NM_003900.5:c.970-59T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003900.5(SQSTM1):​c.970-59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,577,672 control chromosomes in the GnomAD database, including 13,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (4294 hom., cov: 33)
  • Exomes 𝑓: 0.099 (9321 hom.)
• Consequence: SQSTM1 NM_003900.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.238
• Publications: 15 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-179833528-T-C is Benign according to our data. Variant chr5-179833528-T-C is described in ClinVar as Benign. ClinVar VariationId is 1221180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.970-59T>C		intron_variant	Intron 6 of 7	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.718-59T>C		intron_variant	Intron 7 of 8		NP_001135770.1
SQSTM1	NM_001142299.2	c.718-59T>C		intron_variant	Intron 7 of 8		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.970-59T>C		intron_variant	Intron 6 of 7	1	NM_003900.5	ENSP00000374455.4
SQSTM1	ENST00000360718.5	c.718-59T>C		intron_variant	Intron 5 of 6	1		ENSP00000353944.5
SQSTM1	ENST00000510187.5	c.950+301T>C		intron_variant	Intron 6 of 6	5		ENSP00000424477.1
SQSTM1	ENST00000466342.1	n.*142T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28019 AN: 152078 Hom.: 4280 Cov.: 33

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0564

Gnomad FIN AF: 0.0517

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0880

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.0991 AC: 141198 AN: 1425476 Hom.: 9321 Cov.: 28 AF XY: 0.0964 AC XY: 68533 AN XY: 710650

African (AFR) AF: 0.439 AC: 14436 AN: 32868

American (AMR) AF: 0.130 AC: 5740 AN: 44002

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2698 AN: 25842

East Asian (EAS) AF: 0.122 AC: 4798 AN: 39468

South Asian (SAS) AF: 0.0560 AC: 4760 AN: 84938

European-Finnish (FIN) AF: 0.0535 AC: 2798 AN: 52298

Middle Eastern (MID) AF: 0.148 AC: 847 AN: 5724

European-Non Finnish (NFE) AF: 0.0911 AC: 98494 AN: 1081092

Other (OTH) AF: 0.112 AC: 6627 AN: 59244

GnomAD4 genome AF: 0.184 AC: 28078 AN: 152196 Hom.: 4294 Cov.: 33 AF XY: 0.179 AC XY: 13318 AN XY: 74422

African (AFR) AF: 0.423 AC: 17552 AN: 41482

American (AMR) AF: 0.146 AC: 2236 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3472

East Asian (EAS) AF: 0.106 AC: 546 AN: 5166

South Asian (SAS) AF: 0.0562 AC: 271 AN: 4822

European-Finnish (FIN) AF: 0.0517 AC: 549 AN: 10622

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0880 AC: 5983 AN: 68020

Other (OTH) AF: 0.169 AC: 357 AN: 2114

Alfa AF: 0.118 Hom.: 3525

Bravo AF: 0.202

Asia WGS AF: 0.103 AC: 361 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.56
PhyloP100		-0.24
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9
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: rs155788; hg19: chr5-179260528; COSMIC: COSV52976302; COSMIC: COSV52976302;