rs374273620
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_001105206.3(LAMA4):c.392C>T(p.Pro131Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,613,810 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P131P) has been classified as Likely benign.
Frequency
Consequence
NM_001105206.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA4 | NM_001105206.3 | c.392C>T | p.Pro131Leu | missense_variant | 4/39 | ENST00000230538.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.392C>T | p.Pro131Leu | missense_variant | 4/39 | 1 | NM_001105206.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000797 AC: 20AN: 251044Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135680
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461704Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727162
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74298
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1JJ Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 227480). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs374273620, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 131 of the LAMA4 protein (p.Pro131Leu). - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 30, 2015 | p.Pro131Leu in exon 4 of LAMA4: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, several mammals (rhesus, macaque, baboon and pacific walrus) have a leucine (Leu) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. This variant has also been identified in 5/11554 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374273620). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 12, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at