5-179836448-G-C

Variant names:

• chr5-179836448-G-C
• NM_003900.5:c.1178G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003900.5(SQSTM1):​c.1178G>C​(p.Arg393Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86

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]

MRNIP (HGNC:30817): (MRN complex interacting protein) Enables chromatin binding activity. Involved in several processes, including mitotic G2 DNA damage checkpoint signaling; regulation of double-strand break repair; and response to ionizing radiation. Located in nucleoplasm. Colocalizes with Mre11 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.1178G>C	p.Arg393Pro	missense_variant	Exon 8 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.926G>C	p.Arg309Pro	missense_variant	Exon 9 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.926G>C	p.Arg309Pro	missense_variant	Exon 9 of 9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.1178G>C	p.Arg393Pro	missense_variant	Exon 8 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.28		Gain of catalytic residue at P392 (P = 0.0107);.;
MVP		1.0
MPC		0.48
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.87
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-179263448;