rs966588548

Positions:

• chr19-11059826-G-A
• chr19-11059826-G-C
• chr19-11059826-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.4709G>A​(p.Ser1570Asn) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91

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 modified_residue Phosphoserine (size 0) in uniprot entity SMCA4_HUMAN
• 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=0.38366273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4805G>A	p.Ser1602Asn	missense_variant	34/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4709G>A	p.Ser1570Asn	missense_variant	33/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4805G>A	p.Ser1602Asn	missense_variant	34/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4709G>A	p.Ser1570Asn	missense_variant	33/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4715G>A	p.Ser1572Asn	missense_variant	33/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4619G>A	p.Ser1540Asn	missense_variant	33/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4619G>A	p.Ser1540Asn	missense_variant	32/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4619G>A	p.Ser1540Asn	missense_variant	32/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4616G>A	p.Ser1539Asn	missense_variant	33/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4130G>A	p.Ser1377Asn	missense_variant	30/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3359G>A	p.Ser1120Asn	missense_variant	26/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3341G>A	p.Ser1114Asn	missense_variant	25/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3203G>A	p.Ser1068Asn	missense_variant	25/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2969G>A	p.Ser990Asn	missense_variant	23/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.773G>A	p.Ser258Asn	missense_variant	6/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

May 04, 2022

ClinVar contains an entry for this variant (Variation ID: 408690). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1602 of the SMARCA4 protein (p.Ser1602Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.065	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.32	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.75	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.60
MutPred		0.28		.;.;Loss of phosphorylation at S1602 (P = 3e-04);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of phosphorylation at S1602 (P = 3e-04);.;.;.;.;
MVP		0.79
MPC		1.2
ClinPred		0.78	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.69

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: rs966588548; hg19: chr19-11170502;