Genetic Variant NM_003900.5:c.1198C>A (chr5-179836468-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_003900.5(SQSTM1):c.1198C>A(p.Gln400Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q400H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SQSTM1
NM_003900.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.97

Publications

0 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 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_003900.5

PM2

Very rare variant in population databases, with high coverage;

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	UniProt
SQSTM1	NM_003900.5	MANE Select	c.1198C>A	p.Gln400Lys	missense	Exon 8 of 8	NP_003891.1	Q13501-1
SQSTM1	NM_001142298.2		c.946C>A	p.Gln316Lys	missense	Exon 9 of 9	NP_001135770.1	Q13501-2
SQSTM1	NM_001142299.2		c.946C>A	p.Gln316Lys	missense	Exon 9 of 9	NP_001135771.1	Q13501-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SQSTM1	ENST00000389805.9	TSL:1 MANE Select	c.1198C>A	p.Gln400Lys	missense	Exon 8 of 8	ENSP00000374455.4	Q13501-1
SQSTM1	ENST00000360718.5	TSL:1	c.946C>A	p.Gln316Lys	missense	Exon 7 of 7	ENSP00000353944.5	Q13501-2
MRNIP	ENST00000522663.5	TSL:1	n.*1222G>T		non_coding_transcript_exon	Exon 9 of 9	ENSP00000429835.1	F6UWW1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Paget disease of bone 2, early-onset;C5779877:Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

2.0

PhyloP100

5.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.65

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.60

MutPred

0.37

Gain of ubiquitination at Q400 (P = 0.0121)

MVP

0.98

MPC

0.20

ClinPred

0.97

GERP RS

4.8

Varity_R

0.77

gMVP

0.70

Mutation Taster

=20/80

disease causing

(source)

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

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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