rs1060502069

Variant names:

• chr19-11041421-C-A
• rs1060502069
• NM_001387283.1:c.4381C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11041421-C-A
• chr19-11041421-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003072.5(SMARCA4):​c.4285C>A​(p.Arg1429Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,064 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: not found (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: 3.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.35952914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4381C>A	p.Arg1461Ser	missense_variant	Exon 31 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4285C>A	p.Arg1429Ser	missense_variant	Exon 30 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4381C>A	p.Arg1461Ser	missense_variant	Exon 31 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4285C>A	p.Arg1429Ser	missense_variant	Exon 30 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4291C>A	p.Arg1431Ser	missense_variant	Exon 30 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4195C>A	p.Arg1399Ser	missense_variant	Exon 30 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4195C>A	p.Arg1399Ser	missense_variant	Exon 29 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4195C>A	p.Arg1399Ser	missense_variant	Exon 29 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4195C>A	p.Arg1399Ser	missense_variant	Exon 30 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3706C>A	p.Arg1236Ser	missense_variant	Exon 27 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2938C>A	p.Arg980Ser	missense_variant	Exon 23 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2920C>A	p.Arg974Ser	missense_variant	Exon 22 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2779C>A	p.Arg927Ser	missense_variant	Exon 22 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2647C>A	p.Arg883Ser	missense_variant	Exon 21 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.451C>A	p.Arg151Ser	missense_variant	Exon 4 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460064 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726418

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 14, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1461S variant (also known as c.4381C>A), located in coding exon 30 of the SMARCA4 gene, results from a C to A substitution at nucleotide position 4381. The arginine at codon 1461 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	0.043
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.038	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.69	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.80	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.49
MutPred		0.32		.;.;Gain of phosphorylation at R1461 (P = 4e-04);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at R1461 (P = 4e-04);.;.;.;.;.;
MVP		0.67
MPC		1.2
ClinPred		0.79	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.73

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: rs1060502069; hg19: chr19-11152097;