19-11061816-A-T

Variant names:

• chr19-11061816-A-T
• rs772894995
• NM_001387283.1:c.5040A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001387283.1(SMARCA4):​c.5040A>T​(p.Ter1680Cysext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.28
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001387283.1 Downstream stopcodon found after 1736 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.5040A>T	p.Ter1680Cysext*?	stop_lost	Exon 36 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4944A>T	p.Ter1648Cysext*?	stop_lost	Exon 35 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.5040A>T	p.Ter1680Cysext*?	stop_lost	Exon 36 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4944A>T	p.Ter1648Cysext*?	stop_lost	Exon 35 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4950A>T	p.Ter1650Cysext*?	stop_lost	Exon 35 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4854A>T	p.Ter1618Cysext*?	stop_lost	Exon 35 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4854A>T	p.Ter1618Cysext*?	stop_lost	Exon 34 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4854A>T	p.Ter1618Cysext*?	stop_lost	Exon 34 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4851A>T	p.Ter1617Cysext*?	stop_lost	Exon 35 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4365A>T	p.Ter1455Cysext*?	stop_lost	Exon 32 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3594A>T	p.Ter1198Cysext*?	stop_lost	Exon 28 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3576A>T	p.Ter1192Cysext*?	stop_lost	Exon 27 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3438A>T	p.Ter1146Cysext*?	stop_lost	Exon 27 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3204A>T	p.Ter1068Cysext*?	stop_lost	Exon 25 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.1008A>T	p.Ter336Cysext*?	stop_lost	Exon 8 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the SMARCA4 mRNA. It is expected to extend the length of the SMARCA4 protein by 19 additional amino acid residues. 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: 470435). 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. -

not provided Uncertain:1

Sep 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stop codon loss and change to a cysteine codon, leading to protein extension and the addition of 19 amino acids at the C-terminus; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD) -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5040A>T variant (also known as p.*1680Cext*19), located in coding exon 35 of the SMARCA4 gene, results from an A to T substitution at nucleotide position 5040, which is the last nucleotide of the SMARCA4 gene. This alteration disrupts the stop codon of the SMARCA4 gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 19 amino acids. The exact functional effect of the additional amino acids is unknown. 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
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Benign	0.69
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.3
Vest4		0.45
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=64/136	disease causing

Splicing

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

Other links and lift over

dbSNP: rs772894995; hg19: chr19-11172492;