5-179837915-G-T

Variant names:

• chr5-179837915-G-T
• rs1065154
• NM_003900.5:c.*1322G>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003900.5(SQSTM1):​c.*1322G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 1,586,700 control chromosomes in the GnomAD database, including 269,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (35465 hom., cov: 33)
  • Exomes 𝑓: 0.56 (233750 hom.)
• Consequence: SQSTM1 NM_003900.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.678

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-179837915-G-T is Benign according to our data. Variant chr5-179837915-G-T is described in ClinVar as [Benign]. Clinvar id is 353186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SQSTM1	NM_003900.5	c.*1322G>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000389805.9	NP_003891.1
MRNIP	NM_016175.4	c.538-30C>A		intron_variant	Intron 6 of 6	ENST00000292586.11	NP_057259.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SQSTM1	ENST00000389805.9	c.*1322G>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_003900.5	ENSP00000374455.4
MRNIP	ENST00000292586.11	c.538-30C>A		intron_variant	Intron 6 of 6	1	NM_016175.4	ENSP00000292586.6

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101413 AN: 152028 Hom.: 35408 Cov.: 33

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.638 AC: 148240 AN: 232414 Hom.: 49052 AF XY: 0.623 AC XY: 79134 AN XY: 127048

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.802

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.796

Gnomad SAS exome AF: 0.622

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.536

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.564 AC: 809757 AN: 1434554 Hom.: 233750 Cov.: 35 AF XY: 0.565 AC XY: 402229 AN XY: 712294

Gnomad4 AFR exome AF: 0.891

Gnomad4 AMR exome AF: 0.791

Gnomad4 ASJ exome AF: 0.615

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.618

Gnomad4 FIN exome AF: 0.600

Gnomad4 NFE exome AF: 0.530

Gnomad4 OTH exome AF: 0.588

GnomAD4 genome AF: 0.667 AC: 101527 AN: 152146 Hom.: 35465 Cov.: 33 AF XY: 0.671 AC XY: 49942 AN XY: 74386

Gnomad4 AFR AF: 0.875

Gnomad4 AMR AF: 0.719

Gnomad4 ASJ AF: 0.621

Gnomad4 EAS AF: 0.782

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.608

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.638

Alfa AF: 0.561 Hom.: 33478

Bravo AF: 0.685

Asia WGS AF: 0.722 AC: 2512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paget disease of bone 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.73
DANN	Benign	0.66

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: rs1065154; hg19: chr5-179264915;