rs876657378
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM4_SupportingPP3PP5_Moderate
The NM_001387283.1(SMARCA4):c.1636_1638del(p.Lys546del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q544Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
SMARCA4
NM_001387283.1 inframe_deletion
NM_001387283.1 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.23
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_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001387283.1
PM4
?
Nonframeshift variant in NON repetitive region in NM_001387283.1. Strenght limited to Supporting due to length of the change: 1aa.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 19-10996249-CAGA-C is Pathogenic according to our data. Variant chr19-10996249-CAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 30342.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-10996249-CAGA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.1636_1638del | p.Lys546del | inframe_deletion | 10/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.1636_1638del | p.Lys546del | inframe_deletion | 10/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000344626.10 | c.1636_1638del | p.Lys546del | inframe_deletion | 10/35 | 1 | NM_003072.5 | P4 | |
SMARCA4 | ENST00000646693.2 | c.1636_1638del | p.Lys546del | inframe_deletion | 10/36 | NM_001387283.1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 16 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 18, 2012 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2022 | Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 25168959, 23815551, 23010866, 24700502, 24090879, 23637025, 22426308) - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at