chr19-11041512-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_003072.5(SMARCA4):c.4376C>T(p.Thr1459Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1459S) has been classified as Uncertain significance.
Frequency
Consequence
NM_003072.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SMARCA4 | NM_001387283.1 | c.4472C>T | p.Thr1491Ile | missense_variant | Exon 31 of 36 | ENST00000646693.2 | NP_001374212.1 | |
SMARCA4 | NM_003072.5 | c.4376C>T | p.Thr1459Ile | missense_variant | Exon 30 of 35 | ENST00000344626.10 | NP_003063.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SMARCA4 | ENST00000646693.2 | c.4472C>T | p.Thr1491Ile | missense_variant | Exon 31 of 36 | NM_001387283.1 | ENSP00000495368.1 | |||
SMARCA4 | ENST00000344626.10 | c.4376C>T | p.Thr1459Ile | missense_variant | Exon 30 of 35 | 1 | NM_003072.5 | ENSP00000343896.4 | ||
SMARCA4 | ENST00000643549.1 | c.4382C>T | p.Thr1461Ile | missense_variant | Exon 30 of 35 | ENSP00000493975.1 | ||||
SMARCA4 | ENST00000541122.6 | c.4286C>T | p.Thr1429Ile | missense_variant | Exon 30 of 35 | 5 | ENSP00000445036.2 | |||
SMARCA4 | ENST00000643296.1 | c.4286C>T | p.Thr1429Ile | missense_variant | Exon 29 of 34 | ENSP00000496635.1 | ||||
SMARCA4 | ENST00000644737.1 | c.4286C>T | p.Thr1429Ile | missense_variant | Exon 29 of 34 | ENSP00000495548.1 | ||||
SMARCA4 | ENST00000589677.5 | c.4286C>T | p.Thr1429Ile | missense_variant | Exon 30 of 35 | 5 | ENSP00000464778.1 | |||
SMARCA4 | ENST00000643995.1 | c.3797C>T | p.Thr1266Ile | missense_variant | Exon 27 of 32 | ENSP00000496004.1 | ||||
SMARCA4 | ENST00000644963.1 | c.3029C>T | p.Thr1010Ile | missense_variant | Exon 23 of 28 | ENSP00000495599.1 | ||||
SMARCA4 | ENST00000644065.1 | c.3011C>T | p.Thr1004Ile | missense_variant | Exon 22 of 27 | ENSP00000493615.1 | ||||
SMARCA4 | ENST00000642350.1 | c.2870C>T | p.Thr957Ile | missense_variant | Exon 22 of 27 | ENSP00000495355.1 | ||||
SMARCA4 | ENST00000643857.1 | c.2738C>T | p.Thr913Ile | missense_variant | Exon 21 of 25 | ENSP00000494159.1 | ||||
SMARCA4 | ENST00000538456.4 | c.542C>T | p.Thr181Ile | missense_variant | Exon 4 of 8 | 3 | ENSP00000495197.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461656Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727142
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1
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Intellectual disability, autosomal dominant 16 Uncertain:1
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Rhabdoid tumor predisposition syndrome 2 Uncertain:1
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 537775). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1491 of the SMARCA4 protein (p.Thr1491Ile). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.T1491I variant (also known as c.4472C>T), located in coding exon 30 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4472. The threonine at codon 1491 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at