5-179833601-G-A

Variant names:

• chr5-179833601-G-A
• rs146164139
• NM_003900.5:c.984G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003900.5(SQSTM1):​c.984G>A​(p.Ser328Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,614,132 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (22 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.30
• Publications: 3 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: Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Paget disease of bone 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-179833601-G-A is Benign according to our data. Variant chr5-179833601-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00375 (571/152258) while in subpopulation NFE AF = 0.00498 (339/68018). AF 95% confidence interval is 0.00455. There are 3 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003900.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	NM_003900.5	MANE Select	c.984G>A	p.Ser328Ser	synonymous	Exon 7 of 8	NP_003891.1	Q13501-1
	SQSTM1	NM_001142298.2		c.732G>A	p.Ser244Ser	synonymous	Exon 8 of 9	NP_001135770.1	Q13501-2
	SQSTM1	NM_001142299.2		c.732G>A	p.Ser244Ser	synonymous	Exon 8 of 9	NP_001135771.1	Q13501-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.984G>A	p.Ser328Ser	synonymous	Exon 7 of 8	ENSP00000374455.4	Q13501-1
	SQSTM1	ENST00000360718.5	TSL:1	c.732G>A	p.Ser244Ser	synonymous	Exon 6 of 7	ENSP00000353944.5	Q13501-2
	SQSTM1	ENST00000884700.1		c.1008G>A	p.Ser336Ser	synonymous	Exon 7 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152140 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00498

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00446 AC: 1122 AN: 251388 AF XY: 0.00447

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00948

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00411 AC: 6005 AN: 1461874 Hom.: 22 Cov.: 33 AF XY: 0.00413 AC XY: 3000 AN XY: 727240

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00461 AC: 206 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 310 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86256

European-Finnish (FIN) AF: 0.0106 AC: 568 AN: 53416

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00404 AC: 4487 AN: 1111998

Other (OTH) AF: 0.00459 AC: 277 AN: 60396

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00359 AC XY: 267 AN XY: 74444

African (AFR) AF: 0.000842 AC: 35 AN: 41556

American (AMR) AF: 0.00373 AC: 57 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10616

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00498 AC: 339 AN: 68018

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00468 Hom.: 0

Bravo AF: 0.00344

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00468

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)
-	-	1	Paget disease of bone 3 (1)
-	-	1	Paget disease of bone 3;C4225326:Frontotemporal dementia and/or amyotrophic lateral sclerosis 3;C4310693:Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset;C5399975:Myopathy, distal, with rimmed vacuoles (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.0
DANN	Benign	0.86
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs146164139; hg19: chr5-179260601; COSMIC: COSV99481905;