rs372615994
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001105206.3(LAMA4):c.3238C>T(p.Arg1080Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R1080R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001105206.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA4 | NM_001105206.3 | c.3238C>T | p.Arg1080Ter | stop_gained | 24/39 | ENST00000230538.12 | |
LOC107986633 | XR_001744299.2 | n.440-16156G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA4 | ENST00000230538.12 | c.3238C>T | p.Arg1080Ter | stop_gained | 24/39 | 1 | NM_001105206.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251246Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135788
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727228
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1JJ Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 31, 2007 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 27, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2023 | This sequence change creates a premature translational stop signal (p.Arg1073*) in the LAMA4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LAMA4 cause disease. 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. Experimental studies have shown that this premature translational stop signal affects LAMA4 function (PMID: 17646580). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 50369). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 17646580). This variant is present in population databases (rs372615994, gnomAD 0.007%). - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | LAMA4: PM2, PS3:Supporting, PS4:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2023 | Identified in a patient with DCM in published literature (Knoll et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); A published functional study suggests this variant led to decreased endothelial cell adherence compared to wildtype (Knoll et al., 2007); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 23299917, 35526016, 27896284, 34382650, 17646580) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2023 | The p.R1073* variant (also known as c.3217C>T), located in coding exon 23 of the LAMA4 gene, results from a C to T substitution at nucleotide position 3217. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of LAMA4 has not been clearly established as a mechanism of disease. 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