rs143977783

Variant names:

• chr5-179836548-G-A
• rs143977783
• NM_003900.5:c.1278G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003900.5(SQSTM1):​c.1278G>A​(p.Ala426Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: SQSTM1 NM_003900.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.70

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011857212).
• BP6: Variant 5-179836548-G-A is Benign according to our data. Variant chr5-179836548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-179836548-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000355 (54/152150) while in subpopulation AMR AF= 0.0019 (29/15270). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.1278G>A	p.Ala426Ala	synonymous_variant	Exon 8 of 8	ENST00000389805.9	NP_003891.1
SQSTM1	NM_001142298.2	c.1026G>A	p.Ala342Ala	synonymous_variant	Exon 9 of 9		NP_001135770.1
SQSTM1	NM_001142299.2	c.1026G>A	p.Ala342Ala	synonymous_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.1278G>A	p.Ala426Ala	synonymous_variant	Exon 8 of 8	1	NM_003900.5	ENSP00000374455.4

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251496 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135922

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000332 AC: 485 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000312 AC XY: 227 AN XY: 727248

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000368

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74320

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000385

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SQSTM1: BP4, BP7 -

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

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.8
DANN	Benign	0.90
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.048
Sift	Benign	0.041	D
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.33
ClinPred		0.015	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs143977783; hg19: chr5-179263548; COSMIC: COSV99481394; COSMIC: COSV99481394;