19-11021722-C-G

Variant names:

• chr19-11021722-C-G
• rs587777463
• NM_001387283.1:c.2617-3C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003072.5(SMARCA4):​c.2617-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_003072.5 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.39

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-11021722-C-G is Pathogenic according to our data. Variant chr19-11021722-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 139442.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2617-3C>G		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2617-3C>G		splice_region_variant, intron_variant	Intron 18 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2617-3C>G		splice_region_variant, intron_variant	Intron 19 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2029-3C>G		splice_region_variant, intron_variant	Intron 15 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1261-3C>G		splice_region_variant, intron_variant	Intron 11 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1342-3C>G		splice_region_variant, intron_variant	Intron 11 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1102-3C>G		splice_region_variant, intron_variant	Intron 10 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.970-3C>G		splice_region_variant, intron_variant	Intron 9 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Pathogenic:1

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 34
DS_AL_spliceai		0.81		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777463; hg19: chr19-11132398;