rs376158712

chr5-179821042-G-Achr5-179821042-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_003900.5(SQSTM1):c.106G>A(p.Glu36Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,548,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SQSTM1 NM_003900.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.25

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0944272).
• BP6: Variant 5-179821042-G-A is Benign according to our data. Variant chr5-179821042-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 571912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SQSTM1	NM_003900.5	c.106G>A	p.Glu36Lys	missense_variant	1/8	ENST00000389805.9
SQSTM1	NM_001142298.2	c.-47-1916G>A		intron_variant
SQSTM1	NM_001142299.2	c.-47-1916G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SQSTM1	ENST00000389805.9	c.106G>A	p.Glu36Lys	missense_variant	1/8	1	NM_003900.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000153 AC: 24 AN: 156754 Hom.: 0 AF XY: 0.000168 AC XY: 15 AN XY: 89252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.000129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000862

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.0000265 AC: 37 AN: 1396000 Hom.: 0 Cov.: 31 AF XY: 0.0000332 AC XY: 23 AN XY: 692626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000357

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152304 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000820 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000139 AC: 1

ExAC AF: 0.0000789 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;C4085251:Paget disease of bone 2, early-onset Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Benign	0.92
DEOGEN2	Benign	0.28	T;T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.76	T;.;T;.
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.66	N;.;N;N
REVEL	Benign	0.056
Sift	Benign	0.38	T;.;T;T
Sift4G	Benign	0.78	T;T;T;T
Polyphen		0.20	B;.;.;B
Vest4		0.33
MVP		0.89
MPC		0.29
ClinPred		0.037	T
GERP RS		-1.2
Varity_R		0.065
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs376158712; hg19: chr5-179248042;