19-11003063-C-T
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting
The NM_001387283.1(SMARCA4):c.1847C>T(p.Pro616Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P616S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001387283.1 missense
Scores
Clinical Significance
Conservation
Publications
- Coffin-Siris syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
- intellectual disability, autosomal dominant 16Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- rhabdoid tumor predisposition syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
- uterine corpus sarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- familial rhabdoid tumorInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 12 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 12 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 12 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 13 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 12 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 12 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.1847C>T | p.Pro616Leu | missense_variant | Exon 13 of 35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.1259C>T | p.Pro420Leu | missense_variant | Exon 9 of 32 | ENSP00000496004.1 | ||||
SMARCA4 | ENST00000644963.1 | c.491C>T | p.Pro164Leu | missense_variant | Exon 5 of 28 | ENSP00000495599.1 | ||||
SMARCA4 | ENST00000644065.1 | c.572C>T | p.Pro191Leu | missense_variant | Exon 5 of 27 | ENSP00000493615.1 | ||||
SMARCA4 | ENST00000642350.1 | c.332C>T | p.Pro111Leu | missense_variant | Exon 4 of 27 | ENSP00000495355.1 | ||||
SMARCA4 | ENST00000643857.1 | c.200C>T | p.Pro67Leu | missense_variant | Exon 3 of 25 | ENSP00000494159.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152170Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251452 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461788Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32AN XY: 727200 show subpopulations
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338 show subpopulations
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2 Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 616 of the SMARCA4 protein (p.Pro616Leu). This variant is present in population databases (rs755935365, gnomAD 0.008%). This missense change has been observed in individual(s) with neurodevelopmental disorders (PMID: 37500730). ClinVar contains an entry for this variant (Variation ID: 470263). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. 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. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
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Intellectual disability, autosomal dominant 16 Uncertain:1
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not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24658002) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at