rs1000417349

Positions:

• chr19-11039558-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001387283.1(SMARCA4):​c.4266+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,429,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.590

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4266+5G>T		splice_region_variant, intron_variant		ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4171-1749G>T		intron_variant		ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4266+5G>T		splice_region_variant, intron_variant			NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4171-1749G>T		intron_variant		1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4167+5G>T		splice_region_variant, intron_variant				ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4072-1740G>T		intron_variant		5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4072-1740G>T		intron_variant				ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4072-1740G>T		intron_variant				ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4072-1740G>T		intron_variant		5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3583-1740G>T		intron_variant				ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.2815-1740G>T		intron_variant				ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.2797-1740G>T		intron_variant				ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2656-1740G>T		intron_variant				ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2524-1740G>T		intron_variant				ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.328-1740G>T		intron_variant		3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000909 AC: 13 AN: 1429810 Hom.: 0 Cov.: 26 AF XY: 0.0000113 AC XY: 8 AN XY: 710902

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: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change falls in intron 30 of the SMARCA4 gene. It does not directly change the encoded amino acid sequence of the SMARCA4 protein. It affects a nucleotide within the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 470388). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

The c.4266+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 29 in the SMARCA4 gene. This variant has been detected in multiple individuals with no reported features of Coffin-Siris syndrome (Ambry internal data). This nucleotide position is highly conserved on limited sequence alignment. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.030		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: rs1000417349; hg19: chr19-11150234;