NM_003073.5:c.*82C>T

Variant names:

• chr22-23834262-C-T
• rs878854600
• NM_003073.5:c.*82C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_003073.5(SMARCB1):​c.*82C>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 0.000000776 in 1,288,604 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 pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 3_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: -0.109

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

DERL3 (HGNC:14236): (derlin 3) The protein encoded by this gene belongs to the derlin family, and resides in the endoplasmic reticulum (ER). Proteins that are unfolded or misfolded in the ER must be refolded or degraded to maintain the homeostasis of the ER. This protein appears to be involved in the degradation of misfolded glycoproteins in the ER. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-23834262-C-T is Pathogenic according to our data. Variant chr22-23834262-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23834262-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.*82C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000644036.2	NP_003064.2
DERL3	NM_001002862.3	c.*2607G>A		downstream_gene_variant		ENST00000318109.12	NP_001002862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.*82C>T		3_prime_UTR_variant	Exon 9 of 9		NM_003073.5	ENSP00000494049.2
DERL3	ENST00000318109.12	c.*2607G>A		downstream_gene_variant		1	NM_001002862.3	ENSP00000315303.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1288604 Hom.: 0 Cov.: 20 AF XY: 0.00000156 AC XY: 1 AN XY: 640946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the SMARCB1 gene. It does not change the encoded amino acid sequence of the SMARCB1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with schwannomatosis (PMID: 18647326, 22434358, 24933152). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 239481). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SMARCB1 function (PMID: 22949514). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; however, transcript analysis found that SMARCB1 c.*82C>T did not induce abnormal splicing, but the variant was associated with reduced expression (Smith 2012b); This variant is associated with the following publications: (PMID: 22949514, 18647326, 19582488, 19320657, 25631985, 27921248, 25857641, 22434358, 28365909, 24933152) -

Schwannoma;C4024276:Peripheral schwannoma Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 17, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.*82C>T pathogenic mutation is located in the 3' untranslated region (3’ UTR) of the SMARCB1 gene. This variant results from a C to T substitution 82 nucleotides downstream of the last translated codon. This variant has been observed in multiple individuals with diagnosed with schwannomatosis (Boyd C et al. Clin Genet, 2008 Oct;74:358-66; Smith MJ et al. Neurogenetics, 2012 May;13:141-5; Smith MJ et al. Cancer Genet, 2014 Sep;207:373-8; Piotrowski A et al. Hum Mutat, 2022 Jan;43:74-84). It has also been reported to segregate with disease in related individuals (Boyd C et al. Clin Genet, 2008 Oct;74:358-66; Asai K et al. Brain Tumor Pathol, 2015 Jul;32:216-20). This alteration is reported to have reduced expression of the SMARCB1 transcript compared to the wild-type (Smith MJ et al. Hum Mol Genet, 2012 Dec;21:5239-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for SMARCB1-related schwannomatosis and tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown. -

SMARCB1-related schwannomatosis Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs878854600; hg19: chr22-24176449;