rs1429065030

Positions:

• chr19-10996374-AAAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_003072.5(SMARCA4):​c.1759_1761delAAG​(p.Lys587del) variant causes a conservative inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 conservative_inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.23

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003072.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	11/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	10/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1759_1761delAAG	p.Lys587del	conservative_inframe_deletion, splice_region_variant	11/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1171_1173delAAG	p.Lys391del	conservative_inframe_deletion, splice_region_variant	7/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.403_405delAAG	p.Lys135del	conservative_inframe_deletion, splice_region_variant	3/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.487_489delAAG	p.Lys163del	conservative_inframe_deletion, splice_region_variant	3/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.247_249delAAG	p.Lys83del	conservative_inframe_deletion, splice_region_variant	2/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.112_114delAAG	p.Lys38del	conservative_inframe_deletion, splice_region_variant	1/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This variant, c.1759_1761del, results in the deletion of 1 amino acid(s) of the SMARCA4 protein (p.Lys588del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 470256). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 20, 2023	- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 15, 2022

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2024

The c.1759_1761delAAG variant (also known as p.K588del) is located in coding exon 9 of the SMARCA4 gene. This variant results from an in-frame AAG deletion at nucleotide positions 1759 to 1761. This results in the in-frame deletion of a lysine at codon 588. However, this change involves the last codon of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of one amino acid; however, the exact functional impact of the deleted amino acid is unknown at this time (Ambry internal data). This nucleotide position is well conserved in available vertebrate species, and this amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive for protein impact (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1429065030; hg19: chr19-11107050;