chr22-23787169-AATG-A

Position:

• chr22-23787169-AATG-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_003073.5(SMARCB1):​c.10_12del​(p.Met4?) variant causes a start lost, inframe deletion change. The variant allele was found at a frequency of 0.0000243 in 1,602,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SMARCB1 NM_003073.5 start_lost, inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000262 (38/1450158) while in subpopulation AFR AF= 0.000153 (5/32738). AF 95% confidence interval is 0.0000596. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCB1	NM_003073.5	c.10_12del	p.Met4?	start_lost, inframe_deletion	1/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001007468.3	c.10_12del	p.Met4?	start_lost, inframe_deletion	1/9		NP_001007469.1
SMARCB1	NM_001317946.2	c.10_12del	p.Met4?	start_lost, inframe_deletion	1/9		NP_001304875.1
SMARCB1	NM_001362877.2	c.10_12del	p.Met4?	start_lost, inframe_deletion	1/9		NP_001349806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2	c.10_12del	p.Met4?	start_lost, inframe_deletion	1/9		NM_003073.5	ENSP00000494049	A1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151956 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 38 AN: 1450158 Hom.: 0 AF XY: 0.0000249 AC XY: 18 AN XY: 721868

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151956 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74216

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000407 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 10, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 11, 2021

Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has not been reported in the literature in individuals with SMARCB1-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.10_12delATG, results in the deletion of 1 amino acid of the SMARCB1 protein (p.Met4del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs769579890; hg19: chr22-24129356;