rs1555754225

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_003072.5(SMARCA4):​c.803_811delTGCCCCCCG​(p.Val268_Pro270del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000617 in 1,459,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.28
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 Likely_benign. Variant got -2 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_003072.5.
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCA4NM_001387283.1 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/36 ENST00000646693.2 NP_001374212.1
SMARCA4NM_003072.5 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/35 ENST00000344626.10 NP_003063.2 P51532-1A7E2E1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCA4ENST00000646693.2 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/36 NM_001387283.1 ENSP00000495368.1 Q9HBD4
SMARCA4ENST00000344626.10 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/351 NM_003072.5 ENSP00000343896.4 P51532-1
SMARCA4ENST00000643549.1 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/35 ENSP00000493975.1 A0A2R8Y4P4
SMARCA4ENST00000541122.6 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 6/355 ENSP00000445036.2 P51532-4
SMARCA4ENST00000643296.1 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/34 ENSP00000496635.1 P51532-4
SMARCA4ENST00000644737.1 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 5/34 ENSP00000495548.1 P51532-4
SMARCA4ENST00000589677.5 linkc.803_811delTGCCCCCCG p.Val268_Pro270del disruptive_inframe_deletion 6/355 ENSP00000464778.1 P51532-3
SMARCA4ENST00000643995.1 linkc.215_223delTGCCCCCCG p.Val72_Pro74del disruptive_inframe_deletion 2/32 ENSP00000496004.1 A0A2R8YGG3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1459550
Hom.:
0
AF XY:
0.00000826
AC XY:
6
AN XY:
726220
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 14, 2024This variant, c.803_811del, results in the deletion of 3 amino acid(s) of the SMARCA4 protein (p.Val268_Pro270del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 480595). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 13, 2024- -
Intellectual disability, autosomal dominant 16 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 16, 2024In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2024The c.803_811delTGCCCCCCG variant (also known as p.V268_P270del) is located in coding exon 4 of the SMARCA4 gene. This variant results from an in-frame deletion of 9 nucleotides (TGCCCCCCG) at nucleotide positions 803 to 811. This results in the in-frame deletion of 3 amino acids (VPP) at codons 268 to 270. The deleted amino acid positions are well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
SMARCA4-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 12, 2024The SMARCA4 c.803_811del9 variant is predicted to result in an in-frame deletion (p.Val268_Pro270del). 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. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/480595/). 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

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: rs1555754225; hg19: chr19-11097620; API