5-179821034-C-T

Variant names:

• chr5-179821034-C-T
• rs200396166
• NM_003900.5:c.98C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003900.5(SQSTM1):​c.98C>T​(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,554,964 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A33T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2
• Conservation: PhyloP100: 2.76
• Publications: 14 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

ENSG00000301422 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010404259).
• BP6: Variant 5-179821034-C-T is Benign according to our data. Variant chr5-179821034-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 253029.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000735 (112/152306) while in subpopulation NFE AF = 0.00126 (86/68006). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.98C>T	p.Ala33Val	missense	Exon 1 of 8	NP_003891.1	Q13501-1
	SQSTM1	NM_001142298.2		c.-47-1924C>T		intron	N/A	NP_001135770.1	Q13501-2
	SQSTM1	NM_001142299.2		c.-47-1924C>T		intron	N/A	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.98C>T	p.Ala33Val	missense	Exon 1 of 8	ENSP00000374455.4	Q13501-1
	SQSTM1	ENST00000884700.1		c.98C>T	p.Ala33Val	missense	Exon 1 of 8	ENSP00000554759.1
	SQSTM1	ENST00000884698.1		c.98C>T	p.Ala33Val	missense	Exon 1 of 8	ENSP00000554757.1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000813 AC: 137 AN: 168614 AF XY: 0.000845

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000850

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000709

GnomAD4 exome AF: 0.00115 AC: 1617 AN: 1402658 Hom.: 2 Cov.: 31 AF XY: 0.00114 AC XY: 791 AN XY: 696570

African (AFR) AF: 0.000205 AC: 6 AN: 29210

American (AMR) AF: 0.000772 AC: 31 AN: 40158

Ashkenazi Jewish (ASJ) AF: 0.0000808 AC: 2 AN: 24740

East Asian (EAS) AF: 0.00 AC: 0 AN: 34584

South Asian (SAS) AF: 0.000247 AC: 20 AN: 80932

European-Finnish (FIN) AF: 0.00151 AC: 56 AN: 37154

Middle Eastern (MID) AF: 0.00166 AC: 9 AN: 5426

European-Non Finnish (NFE) AF: 0.00131 AC: 1431 AN: 1092168

Other (OTH) AF: 0.00106 AC: 62 AN: 58286

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152306 Hom.: 0 Cov.: 34 AF XY: 0.000698 AC XY: 52 AN XY: 74476

African (AFR) AF: 0.000265 AC: 11 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10616

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000744

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000812 AC: 6

ExAC AF: 0.000679 AC: 78

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.69	N
PhyloP100		2.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.049
Sift	Benign	0.42	T
Sift4G	Benign	0.54	T
Polyphen		0.0080	B
Vest4		0.30
MVP		0.88
MPC		0.13
ClinPred		0.028	T
GERP RS		0.80
PromoterAI		-0.0083	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.078
gMVP		0.35
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200396166; hg19: chr5-179248034; COSMIC: COSV62435009; COSMIC: COSV62435009;