rs878854228

Variant names:

• chr19-11059743-C-A
• rs878854228
• NM_001387283.1:c.4732-10C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11059743-C-A
• chr19-11059743-C-G
• chr19-11059743-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_003072.5(SMARCA4):​c.4636-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,407,054 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 intron
• Scores: Splicing: ADA: 0.005246
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.428

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4732-10C>A		intron_variant	Intron 33 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4636-10C>A		intron_variant	Intron 32 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4732-10C>A		intron_variant	Intron 33 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4636-10C>A		intron_variant	Intron 32 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4642-10C>A		intron_variant	Intron 32 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4546-10C>A		intron_variant	Intron 32 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4546-10C>A		intron_variant	Intron 31 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4546-10C>A		intron_variant	Intron 31 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4543-10C>A		intron_variant	Intron 32 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4057-10C>A		intron_variant	Intron 29 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3286-10C>A		intron_variant	Intron 25 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3268-10C>A		intron_variant	Intron 24 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3130-10C>A		intron_variant	Intron 24 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2896-10C>A		intron_variant	Intron 22 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.700-10C>A		intron_variant	Intron 5 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1407054 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 694826

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: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1 Benign:1

Jul 25, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SMARCA4-related disorder Uncertain:1

Aug 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMARCA4 c.4732-10C>A variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/537794/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0052
dbscSNV1_RF	Benign	0.044
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878854228; hg19: chr19-11170419;