chr19-11018981-G-C

Variant names:

• chr19-11018981-G-C
• rs375459615
• NM_001387283.1:c.2463G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001387283.1(SMARCA4):​c.2463G>C​(p.Glu821Asp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E821E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.355
• 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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001387283.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 19-11018981-G-C is Pathogenic according to our data. Variant chr19-11018981-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1809733.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2463G>C	p.Glu821Asp	missense_variant	Exon 18 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2463G>C	p.Glu821Asp	missense_variant	Exon 17 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2463G>C	p.Glu821Asp	missense_variant	Exon 18 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1875G>C	p.Glu625Asp	missense_variant	Exon 14 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1107G>C	p.Glu369Asp	missense_variant	Exon 10 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1188G>C	p.Glu396Asp	missense_variant	Exon 10 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.948G>C	p.Glu316Asp	missense_variant	Exon 9 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.816G>C	p.Glu272Asp	missense_variant	Exon 8 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 27, 2021

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been confirmed to occur de novo in an individual tested at Athena Diagnostics, who had clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;T;D;.;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H;.;.;.;H;H;.;H;H;H;H;H;H;H;H;H;.;.;.;.;.;.
PhyloP100		-0.35
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	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		0.90
MutPred		0.89		Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);Loss of MoRF binding (P = 0.2474);.;Loss of MoRF binding (P = 0.2474);.;.;.;.;
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.99
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375459615; hg19: chr19-11129657;