19-11021722-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001387283.1(SMARCA4):c.2617-3C>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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA4
NM_001387283.1 splice_region, intron

Scores

Splicing: ADA: 0.03913

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.39

Publications

2 publications found

Variant links:

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

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

240436

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723704

African (AFR)

AF:

0.00

AC:

AN:

33328

American (AMR)

AF:

0.00

AC:

AN:

43972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39384

South Asian (SAS)

AF:

0.00

AC:

AN:

85702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109016

Other (OTH)

AF:

0.00

AC:

AN:

60186

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 23, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2617-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 18 in the SMARCA4 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. 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

-0.41

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

2.4

PromoterAI

-0.0043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.039

dbscSNV1_RF

Benign

0.41

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over