rs745740277

Variant names:

• chr19-11060181-AGAG-A
• rs745740277
• ENST00000646693.2:c.4994_4996delGAG

Your query was ambiguous. Multiple possible variants found:

• chr19-11060181-AGAG-A
• chr19-11060181-AGAG-AGAGGAG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The ENST00000646693.2(SMARCA4):​c.4994_4996delGAG​(p.Glu1666del) variant causes a disruptive inframe deletion 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. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E1665E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: SMARCA4 ENST00000646693.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000646693.2. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5006_5007+1delAGG	p.Glu1669AspfsTer11	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 35 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4910_4911+1delAGG	p.Glu1637AspfsTer11	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 34 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4994_4996delGAG	p.Glu1666del	disruptive_inframe_deletion	Exon 35 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4898_4900delGAG	p.Glu1634del	disruptive_inframe_deletion	Exon 34 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4904_4906delGAG	p.Glu1636del	disruptive_inframe_deletion	Exon 34 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4808_4810delGAG	p.Glu1604del	disruptive_inframe_deletion	Exon 34 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4808_4810delGAG	p.Glu1604del	disruptive_inframe_deletion	Exon 33 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4808_4810delGAG	p.Glu1604del	disruptive_inframe_deletion	Exon 33 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4805_4807delGAG	p.Glu1603del	disruptive_inframe_deletion	Exon 34 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4319_4321delGAG	p.Glu1441del	disruptive_inframe_deletion	Exon 31 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3548_3550delGAG	p.Glu1184del	disruptive_inframe_deletion	Exon 27 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3530_3532delGAG	p.Glu1178del	disruptive_inframe_deletion	Exon 26 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3392_3394delGAG	p.Glu1132del	disruptive_inframe_deletion	Exon 26 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3158_3160delGAG	p.Glu1054del	disruptive_inframe_deletion	Exon 24 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.962_964delGAG	p.Glu322del	disruptive_inframe_deletion	Exon 7 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 155058 AF XY: 0.0000122

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31574

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078646

Other (OTH) AF: 0.00 AC: 0 AN: 57936

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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+1del. 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. -

Oct 26, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

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

Other links and lift over

dbSNP: rs745740277; hg19: chr19-11170857;