NM_001387283.1:c.2616+2_2616+5dupTAAC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001387283.1(SMARCA4):​c.2616+2_2616+5dupTAAC variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SMARCA4
NM_001387283.1 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.92
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.2616+2_2616+5dupTAAC splice_region_variant, intron_variant Intron 18 of 35 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.2616+2_2616+5dupTAAC splice_region_variant, intron_variant Intron 18 of 34 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 18 of 35 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 18 of 34 1 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 18 of 34 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 19 of 34 5 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 18 of 33 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 18 of 33 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.2616+1_2616+2insTAAC splice_donor_variant, intron_variant Intron 19 of 34 5 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.2028+1_2028+2insTAAC splice_donor_variant, intron_variant Intron 15 of 31 ENSP00000496004.1 A0A2R8YGG3
SMARCA4ENST00000644963.1 linkc.1260+1_1260+2insTAAC splice_donor_variant, intron_variant Intron 11 of 27 ENSP00000495599.1 A0A2R8YG32
SMARCA4ENST00000644065.1 linkc.1341+1_1341+2insTAAC splice_donor_variant, intron_variant Intron 11 of 26 ENSP00000493615.1 A0A2R8Y440
SMARCA4ENST00000642350.1 linkc.1101+1_1101+2insTAAC splice_donor_variant, intron_variant Intron 10 of 26 ENSP00000495355.1 A0A2R8Y6N0
SMARCA4ENST00000643857.1 linkc.969+1_969+2insTAAC splice_donor_variant, intron_variant Intron 9 of 24 ENSP00000494159.1 A0A2R8Y526

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Feb 24, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 18 of the SMARCA4 gene. It does not directly change the encoded amino acid sequence of the SMARCA4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related disease. Nucleotide substitutions within 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 is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555777830; hg19: chr19-11130378; API