rs745740277

Positions:

• chr19-11060181-AGAG-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_003072.5(SMARCA4):​c.4910_4911+1delAGG​(p.Glu1637fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,398,584 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: 0.0000086 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.81

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00688 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5006_5007+1delAGG	p.Glu1669fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	35/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4910_4911+1delAGG	p.Glu1637fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	34/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.5006_5007+1delAGG	p.Glu1669fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	35/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4910_4911+1delAGG	p.Glu1637fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	34/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4916_4917+1delAGG	p.Glu1639fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	34/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4820_4821+1delAGG	p.Glu1607fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	34/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4820_4821+1delAGG	p.Glu1607fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	33/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4820_4821+1delAGG	p.Glu1607fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	33/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4817_4818+1delAGG	p.Glu1606fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	34/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4331_4332+1delAGG	p.Glu1444fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	31/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3560_3561+1delAGG	p.Glu1187fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	27/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3542_3543+1delAGG	p.Glu1181fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	26/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3404_3405+1delAGG	p.Glu1135fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	26/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3170_3171+1delAGG	p.Glu1057fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	24/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.974_975+1delAGG	p.Glu325fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	7/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000129 AC: 2 AN: 155058 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 81774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000337

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398584 Hom.: 0 AF XY: 0.0000116 AC XY: 8 AN XY: 689822

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: 0.0000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

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	Baylor Genetics	Oct 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This variant, c.5005_5007delGAG, results in the deletion of 1 amino acid(s) of the SMARCA4 protein (p.Glu1669del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745740277, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is also known as c.5006_5007+1delAGG. ClinVar contains an entry for this variant (Variation ID: 470432). 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. -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2024

Canonical splice site variant with an unclear effect on protein function; In silico analysis supports a deleterious effect on splicing: cryptic splice site predicted to result in an in-frame deletion at the protein level (E1669del); Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.5006_5007+1delAGG variant results from a deletion of the last two nucleotides of coding exon 34 and the first nucleotide of intron 34. These nucleotide positions are highly conserved in available vertebrate species. 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 1 amino acid; however, the exact functional impact of the deleted amino acid is unknown at this time (Ambry internal data). This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

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: rs745740277; hg19: chr19-11170857;