rs727503113
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001105206.3(LAMA4):c.412C>T(p.His138Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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. H138H) has been classified as Likely benign.
Frequency
Consequence
NM_001105206.3 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathy 1JJInheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LAMA4 | NM_001105206.3 | c.412C>T | p.His138Tyr | missense_variant | Exon 4 of 39 | ENST00000230538.12 | NP_001098676.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.412C>T | p.His138Tyr | missense_variant | Exon 4 of 39 | 1 | NM_001105206.3 | ENSP00000230538.7 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152110Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251058 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461668Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30AN XY: 727128 show subpopulations
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74302 show subpopulations
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1JJ Uncertain:1
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 tyrosine 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: 163796). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs727503113, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 138 of the LAMA4 protein (p.His138Tyr). -
not provided Uncertain:1
Identified in a patient with HCM in published literature (Burstein et al., 2021); this patient harbored additional cardiogenetic variants; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32746448) -
Cardiovascular phenotype Uncertain:1
The p.H138Y variant (also known as c.412C>T), located in coding exon 3 of the LAMA4 gene, results from a C to T substitution at nucleotide position 412. The histidine at codon 138 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, tyrosine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Benign:1
His138Tyr in exon 4 of LAMA4: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, multiple mammals have a tyrosine (Tyr) at this position despite high nearby a mino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen 2, SIFT) do not suggest a high likelihood of impact to the protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at