19-10989417-C-T

Variant names:

• chr19-10989417-C-T
• rs1060502078
• NM_001387283.1:c.1219C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387283.1(SMARCA4):​c.1219C>T​(p.Leu407Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L407L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.02
• Publications: 1 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 2 ACMG points.

• 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.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1219C>T	p.Leu407Phe	missense_variant	Exon 8 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1219C>T	p.Leu407Phe	missense_variant	Exon 7 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1219C>T	p.Leu407Phe	missense_variant	Exon 8 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.631C>T	p.Leu211Phe	missense_variant	Exon 4 of 32			ENSP00000496004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Oct 23, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. This sequence change replaces leucine with phenylalanine at codon 407 of the SMARCA4 protein (p.Leu407Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L407F variant (also known as c.1219C>T), located in coding exon 6 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 1219. The leucine at codon 407 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) 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). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
PhyloP100		5.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Uncertain	0.039	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		0.98	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.70
MutPred		0.53		Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);Loss of catalytic residue at L407 (P = 0.0057);
MVP		0.68
MPC		2.5
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.83
gMVP		0.99
Mutation Taster		=28/72	disease causing

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: rs1060502078; hg19: chr19-11100093;