Genetic Variant NM_003900.5:c.1245G>T (chr5-179836515-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003900.5(SQSTM1):c.1245G>T(p.Arg415Ser) 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. 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. R415G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.285

Publications

3 publications found

Variant links:

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 links:

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]

MRNIP links:

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ACMG classification

Classification was made for transcript

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=0.12083432).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SQSTM1	NM_003900.5	MANE Select	c.1245G>T	p.Arg415Ser	missense	Exon 8 of 8	NP_003891.1
SQSTM1	NM_001142298.2		c.993G>T	p.Arg331Ser	missense	Exon 9 of 9	NP_001135770.1
SQSTM1	NM_001142299.2		c.993G>T	p.Arg331Ser	missense	Exon 9 of 9	NP_001135771.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.1245G>T	p.Arg415Ser	missense	Exon 8 of 8	ENSP00000374455.4
SQSTM1	ENST00000360718.5	TSL:1	c.993G>T	p.Arg331Ser	missense	Exon 7 of 7	ENSP00000353944.5
MRNIP	ENST00000522663.5	TSL:1	n.*1175C>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000429835.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

Eigen

Benign

-0.018

Eigen_PC

Benign

-0.024

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.033

MetaRNN

Benign

0.12

MetaSVM

Uncertain

-0.28

PhyloP100

-0.28

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.093

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Polyphen

0.075

Vest4

0.19

MutPred

0.12

Loss of relative solvent accessibility (P = 0.0071)

MVP

0.53

ClinPred

0.94

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

Mutation Taster

=24/76

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over