5-179833213-G-C

Variant names:

• chr5-179833213-G-C
• rs4797
• NM_003900.5:c.936G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003900.5(SQSTM1):​c.936G>C​(p.Arg312Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 51 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09810516).

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.936G>C	p.Arg312Ser	missense	Exon 6 of 8	NP_003891.1	Q13501-1
	SQSTM1	NM_001142298.2		c.684G>C	p.Arg228Ser	missense	Exon 7 of 9	NP_001135770.1	Q13501-2
	SQSTM1	NM_001142299.2		c.684G>C	p.Arg228Ser	missense	Exon 7 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.936G>C	p.Arg312Ser	missense	Exon 6 of 8	ENSP00000374455.4	Q13501-1
	SQSTM1	ENST00000360718.5	TSL:1	c.684G>C	p.Arg228Ser	missense	Exon 5 of 7	ENSP00000353944.5	Q13501-2
	SQSTM1	ENST00000884700.1		c.960G>C	p.Arg320Ser	missense	Exon 6 of 8	ENSP00000554759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.27
DANN	Benign	0.74
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.0
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.14
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.0020	B
Vest4		0.060
MutPred		0.36		Gain of phosphorylation at R312 (P = 0.0365)
MVP		0.72
MPC		0.15
ClinPred		0.057	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.078
gMVP		0.13
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4797; hg19: chr5-179260213;