rs781939403
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001105206.3(LAMA4):c.1436A>T(p.Asp479Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001105206.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA4 | NM_001105206.3 | c.1436A>T | p.Asp479Val | missense_variant | 12/39 | ENST00000230538.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.1436A>T | p.Asp479Val | missense_variant | 12/39 | 1 | NM_001105206.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251306Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461790Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727196
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74318
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1JJ Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 11, 2016 | In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is present in population databases (rs781939403, ExAC <0.01%) but has not been reported in the literature in individuals with a LAMA4-related disease. ClinVar contains an entry for this variant (Variation ID: 213612). This sequence change replaces aspartic acid with valine at codon 472 of the LAMA4 protein (p.Asp472Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2018 | p.Asp472Val (GAT>GTT): c.1415 A>T in exon 12 of the LAMA4 gene (NM_002290.3). A variant of unknown significance has been identified in the LAMA4 gene. The D472V variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The D472V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D472V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammalian species. Nevertheless, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in CARDIOMYOPATHY - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 21, 2022 | The p.D472V variant (also known as c.1415A>T), located in coding exon 11 of the LAMA4 gene, results from an A to T substitution at nucleotide position 1415. The aspartic acid at codon 472 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at