rs568390760
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2
The NM_001387283.1(SMARCA4):βc.722_733delβ(p.Gly241_Pro244del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000129 in 1,540,212 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (β β ). Synonymous variant affecting the same amino acid position (i.e. P238P) has been classified as Likely benign.
Frequency
Genomes: π 0.00056 ( 0 hom., cov: 32)
Exomes π: 0.000081 ( 1 hom. )
Consequence
SMARCA4
NM_001387283.1 inframe_deletion
NM_001387283.1 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.17
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 Benign. Variant got -17 ACMG points.
BP3
?
Nonframeshift variant in repetitive region in NM_001387283.1
BP6
?
Variant 19-10986544-CCCCGGCCCGGGT-C is Benign according to our data. Variant chr19-10986544-CCCCGGCCCGGGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 238517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10986544-CCCCGGCCCGGGT-C is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000565 (86/152222) while in subpopulation AFR AF= 0.00195 (81/41552). AF 95% confidence interval is 0.00161. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 86 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.722_733del | p.Gly241_Pro244del | inframe_deletion | 4/36 | ENST00000646693.2 | |
SMARCA4 | NM_003072.5 | c.722_733del | p.Gly241_Pro244del | inframe_deletion | 4/35 | ENST00000344626.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000344626.10 | c.722_733del | p.Gly241_Pro244del | inframe_deletion | 4/35 | 1 | NM_003072.5 | P4 | |
SMARCA4 | ENST00000646693.2 | c.722_733del | p.Gly241_Pro244del | inframe_deletion | 4/36 | NM_001387283.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000104 AC: 14AN: 134992Hom.: 0 AF XY: 0.0000542 AC XY: 4AN XY: 73738
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GnomAD4 exome AF: 0.0000814 AC: 113AN: 1387990Hom.: 1 AF XY: 0.0000657 AC XY: 45AN XY: 684998
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GnomAD4 genome ? AF: 0.000565 AC: 86AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40AN XY: 74412
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2022 | See Variant Classification Assertion Criteria. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The SMARCA4 p.Gly241_Pro244del variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs568390760) and in ClinVar (classified as likely benign by Genetic Services Laboratory University of Chicago and Ambry Genetics and as VUS by Invitae). The variant was identified in control databases in 27 of 166304 chromosomes at a frequency of 0.000162 (Genome Aggregation Database Feb 27, 2017). The variant was found in the following populations: African in 22 of 15130 chromosomes (freq: 0.001454), Other in 2 of 5186 chromosomes (freq: 0.000386) and Latino in 3 of 25264 chromosomes (freq: 0.000119), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant is an in-frame deletion resulting in the removal of codons 241 to 244 in a proline-glycine repeat region, however the impact of this alteration on the SMARCA4 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 29, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 22, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Benign:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 14, 2016 | - - |
Rhabdoid tumor predisposition syndrome 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at