rs1555787120

Variant names:

• chr19-11039467-GG-C
• rs1555787120
• NM_001387283.1:c.4180_4181delGGinsC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001387283.1(SMARCA4):​c.4180_4181delGGinsC​(p.Gly1394GlnfsTer101) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1394A) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 frameshift, missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.730
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4180_4181delGGinsC	p.Gly1394GlnfsTer101	frameshift_variant, missense_variant	Exon 30 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4171-1840_4171-1839delGGinsC		intron_variant	Intron 29 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4180_4181delGGinsC	p.Gly1394GlnfsTer101	frameshift_variant, missense_variant	Exon 30 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000643549.1	c.4081_4082delGGinsC	p.Gly1361GlnfsTer31	frameshift_variant, missense_variant	Exon 29 of 35			ENSP00000493975.1
SMARCA4	ENST00000344626.10	c.4171-1840_4171-1839delGGinsC		intron_variant	Intron 29 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000541122.6	c.4072-1831_4072-1830delGGinsC		intron_variant	Intron 29 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4072-1831_4072-1830delGGinsC		intron_variant	Intron 28 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4072-1831_4072-1830delGGinsC		intron_variant	Intron 28 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4072-1831_4072-1830delGGinsC		intron_variant	Intron 29 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3583-1831_3583-1830delGGinsC		intron_variant	Intron 26 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2815-1831_2815-1830delGGinsC		intron_variant	Intron 22 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2797-1831_2797-1830delGGinsC		intron_variant	Intron 21 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2656-1831_2656-1830delGGinsC		intron_variant	Intron 21 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2524-1831_2524-1830delGGinsC		intron_variant	Intron 20 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.328-1831_328-1830delGGinsC		intron_variant	Intron 3 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly1394Glnfs*101) in the SMARCA4 gene. Loss-of-function variants in SMARCA4 are known to be pathogenic (PMID: 24658001, 24658002). However, tissue-specific alternative splicing of SMARCA4 gene results in functional isoforms lacking in-frame exon 30 (also known as exon 28B, PMID: 18437052). For this reason the clinical significance of loss of function variants in exon 30 is currently uncertain. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with epthelial ovarian cancer (PMID: 29204511). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4180_4181delGGinsC variant, located in coding exon 29 of the SMARCA4 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.G1394Qfs*101). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in SMARCA4 are known to cause rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT); however, such associations with neurodevelopmental disorders are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). However, this region of the SMARCA4 gene is excluded from other biologically relevant transcripts. 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		0.73
Mutation Taster		=12/188	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555787120; hg19: chr19-11150143;