19-11018981-G-C

Position:

• chr19-11018981-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_003072.5(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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.355

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 165) in uniprot entity SMCA4_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003072.5
• 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, 0.986
• 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/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2463G>C	p.Glu821Asp	missense_variant	17/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2463G>C	p.Glu821Asp	missense_variant	17/35	ENST00000344626.10	NP_003063.2

Ensembl

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 27, 2021

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;.;.;.;.;.;.
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11129657;