rs878854210

Positions:

• chr19-11019618-G-A
• chr19-11019618-G-C
• chr19-11019618-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_003072.5(SMARCA4):​c.2533G>A​(p.Val845Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Sufficient for interaction with DLX1 (size 79) in uniprot entity SMCA4_HUMAN there are 7 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26700455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2533G>A	p.Val845Ile	missense_variant	18/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2533G>A	p.Val845Ile	missense_variant	18/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2533G>A	p.Val845Ile	missense_variant	18/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2533G>A	p.Val845Ile	missense_variant	18/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2533G>A	p.Val845Ile	missense_variant	18/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2533G>A	p.Val845Ile	missense_variant	19/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2533G>A	p.Val845Ile	missense_variant	18/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2533G>A	p.Val845Ile	missense_variant	18/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2533G>A	p.Val845Ile	missense_variant	19/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1945G>A	p.Val649Ile	missense_variant	15/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1177G>A	p.Val393Ile	missense_variant	11/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1258G>A	p.Val420Ile	missense_variant	11/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1018G>A	p.Val340Ile	missense_variant	10/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.886G>A	p.Val296Ile	missense_variant	9/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460412 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726364

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMARCA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 845 of the SMARCA4 protein (p.Val845Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	-0.25	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.82	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.25	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.;.
Sift4G	Benign	0.13	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.27	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.11
MutPred		0.36		Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);Loss of MoRF binding (P = 0.1027);.;Loss of MoRF binding (P = 0.1027);.;.;.;.;
MVP		0.65
MPC		2.2
ClinPred		0.74	D
GERP RS		4.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.12
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs878854210; hg19: chr19-11130294;