6-112172772-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001105206.3(LAMA4):c.1390C>G(p.His464Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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.1390C>G | p.His464Asp | missense_variant | 12/39 | ENST00000230538.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.1390C>G | p.His464Asp | missense_variant | 12/39 | 1 | NM_001105206.3 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251092Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135762
GnomAD4 exome AF: 0.0000841 AC: 123AN: 1461730Hom.: 0 Cov.: 33 AF XY: 0.0000825 AC XY: 60AN XY: 727176
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74318
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1JJ Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 44346). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs151119304, gnomAD 0.01%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 457 of the LAMA4 protein (p.His457Asp). - |
not provided Benign:2
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 13, 2013 | Variant classified as Uncertain Significance - Favor Benign. The His457Asp varia nt in LAMA4 has not been reported in the literature, but has been identified by our laboratory in 1 individual with HCM, who also carried another variant likely to be disease-causing (LMM unpublished data). This variant is listed in dbSNP w ithout frequency information (dbSNP rs151119304) and has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), though it may be co mmon in other populations. Histidine (His) at position 457 is not well conserved in evolution, including in mammals, which suggests that a change at this positi on may be tolerated. Other computational analyses (biochemical amino acid proper ties, AlignGVGD, PolyPhen2, and SIFT) also suggest that the variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, the available data suggests that this variant is more li kely benign, but additional studies are needed to fully assess the clinical sign ificance of the His457Asp variant. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 11, 2018 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 06, 2024 | 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