19-11023594-G-A

Position:

• chr19-11023594-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_003072.5(SMARCA4):​c.2936G>A​(p.Arg979Gln) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 9.76

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 19-11023594-G-A is Pathogenic according to our data. Variant chr19-11023594-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212246.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=5, Likely_pathogenic=2}. Variant chr19-11023594-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2936G>A	p.Arg979Gln	missense_variant	20/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2936G>A	p.Arg979Gln	missense_variant	20/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2936G>A	p.Arg979Gln	missense_variant	20/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2936G>A	p.Arg979Gln	missense_variant	20/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2936G>A	p.Arg979Gln	missense_variant	20/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2936G>A	p.Arg979Gln	missense_variant	21/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2936G>A	p.Arg979Gln	missense_variant	20/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2936G>A	p.Arg979Gln	missense_variant	20/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2936G>A	p.Arg979Gln	missense_variant	21/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2348G>A	p.Arg783Gln	missense_variant	17/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1580G>A	p.Arg527Gln	missense_variant	13/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1661G>A	p.Arg554Gln	missense_variant	13/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1421G>A	p.Arg474Gln	missense_variant	12/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1289G>A	p.Arg430Gln	missense_variant	11/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 27, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant was previously reported as a de novo change in a male with Coffin Siri syndrome [PMID:28973083] -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease is not clearly established for Coffin-Siris syndrome 4 (MIM#614609). However, susceptibility to rhabdoid tumor predisposition syndrome 2 (MIM#613325) is caused by loss of function variants (OMIM, PMID: 22426308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported mostly as likely pathogenic and pathogenic, and has been observed in multiple de novo individuals with Coffin-Siris syndrome, intellectual disability and/or cleft palate (Decipher, ClinVar, PMID: 28973083). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cleft palate Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Autoinflammatory diseases unit, CHU de Montpellier

Dec 03, 2018

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Jan 05, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

De novo variant with confirmed parentage in a critically ill infant, but no clinical information provided (Meng et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28973083, 32686290, 24658002, 33144586, 34930489) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2024

The p.R979Q pathogenic mutation (also known as c.2936G>A), located in coding exon 19 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 2936. The arginine at codon 979 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in multiple individuals with features consistent with Coffin-Siris Syndrome, and the variant was reported as a de novo change in several of these individuals (Meng L et al. JAMA Pediatr, 2017 Dec;171:e173438; Li D et al. Am J Med Genet A, 2020 Sep;182:2058-2067; Domogala DD et al. Hum Genomics, 2021 Dec;15:72; Gofin Y et al. Am J Med Genet A, 2022 Sep;188:2718-2723). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, this alteration is pathogenic for Coffin-Siris syndrome; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

SMARCA4-related BAFopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;H;H;.;H;H;H;H;H;H;H;H;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.97
MutPred		0.90		Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);Loss of MoRF binding (P = 0.0568);.;Loss of MoRF binding (P = 0.0568);.;.;.;.;
MVP		0.97
MPC		3.5
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.93
gMVP		1.0

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: rs797045981; hg19: chr19-11134270; COSMIC: COSV100758931; COSMIC: COSV100758931;