dbSNP rs878854600: SMARCB1:c.*82C>A (chr22-23834262-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003073.5(SMARCB1):c.*82C>A 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 1,288,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

SMARCB1
NM_003073.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.109

Publications

0 publications found

Variant links:

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]

SMARCB1 links:

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]

DERL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCB1	NM_003073.5 link	c.*82C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000644036.2	NP_003064.2	Q12824-1
DERL3	NM_001002862.3 link	c.*2607G>T		downstream_gene_variant		ENST00000318109.12	NP_001002862.1	Q96Q80-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 link	c.*82C>A		3_prime_UTR_variant	Exon 9 of 9		NM_003073.5	ENSP00000494049.2		Q12824-1
DERL3	ENST00000318109.12 link	c.*2607G>T		downstream_gene_variant		1	NM_001002862.3	ENSP00000315303.8		Q96Q80-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.76e-7

AC:

AN:

1288598

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

640942

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29448

American (AMR)

AF:

0.00

AC:

AN:

35656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24546

East Asian (EAS)

AF:

0.00

AC:

AN:

35206

South Asian (SAS)

AF:

0.00

AC:

AN:

77210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.00000102

AC:

AN:

982342

Other (OTH)

AF:

0.00

AC:

AN:

54506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

-0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over