19-10996385-G-T

Variant names:

• chr19-10996385-G-T
• rs1555763822
• NM_001387283.1:c.1761+5G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001387283.1(SMARCA4):​c.1761+5G>T 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA4 NM_001387283.1 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
• intellectual disability, autosomal dominant 16

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• rhabdoid tumor predisposition syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• uterine corpus sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• familial rhabdoid tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 35	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 34	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 35		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 34	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 34			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1761+5G>T		splice_region_variant, intron_variant	Intron 11 of 34	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 33			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1761+5G>T		splice_region_variant, intron_variant	Intron 10 of 33			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1761+5G>T		splice_region_variant, intron_variant	Intron 11 of 34	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1173+5G>T		splice_region_variant, intron_variant	Intron 7 of 31			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.405+5G>T		splice_region_variant, intron_variant	Intron 3 of 27			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.489+5G>T		splice_region_variant, intron_variant	Intron 3 of 26			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.249+5G>T		splice_region_variant, intron_variant	Intron 2 of 26			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.114+5G>T		splice_region_variant, intron_variant	Intron 1 of 24			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1761+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 9 in the SMARCA4 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. 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
BayesDel_noAF	Benign	-0.79
CADD	Benign	18
DANN	Benign	0.65
PhyloP100		2.0
PromoterAI		0.0038	Neutral
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555763822; hg19: chr19-11107061;