5-179824086-A-G

Position:

• chr5-179824086-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000389805.9(SQSTM1):​c.530A>G​(p.Glu177Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E177A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SQSTM1 ENST00000389805.9 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.530A>G	p.Glu177Gly	missense_variant, splice_region_variant	3/8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.278A>G	p.Glu93Gly	missense_variant, splice_region_variant	4/9		NP_001135770.1
SQSTM1	NM_001142299.2	c.278A>G	p.Glu93Gly	missense_variant, splice_region_variant	4/9		NP_001135771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.530A>G	p.Glu177Gly	missense_variant, splice_region_variant	3/8	1	NM_003900.5	ENSP00000374455	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	.;.;T;T;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.099
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.1	.;.;M;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;D;D;N;D
REVEL	Benign	0.21
Sift	Uncertain	0.019	D;D;D;D;D
Sift4G	Benign	0.086	T;T;T;D;T
Polyphen		0.0030, 0.68	.;.;B;P;.
Vest4		0.74, 0.68, 0.74
MutPred		0.30		.;.;Gain of glycosylation at S176 (P = 0.0218);Gain of glycosylation at S176 (P = 0.0218);.;
MVP		0.96
MPC		0.17
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

LitVar

Other links and lift over

dbSNP: rs1392938040; hg19: chr5-179251086;