rs759155854
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000426.4(LAMA2):c.5072-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000426.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.5072-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000421865.3 | |||
LAMA2 | NM_001079823.2 | c.5072-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.5072-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000426.4 | ||||
LAMA2 | ENST00000617695.5 | c.5072-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
LAMA2 | ENST00000618192.5 | c.5336-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | P1 | ||||
LAMA2 | ENST00000687590.1 | n.1492-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249604Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135392
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460340Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726534
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 08, 2018 | - - |
LAMA2-related muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2022 | This sequence change falls in intron 35 of the LAMA2 gene. It does not directly change the encoded amino acid sequence of the LAMA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs759155854, gnomAD 0.006%). This variant has been observed in individual(s) with limb-girdle muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 355275). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Congenital muscular dystrophy due to partial LAMA2 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | Dec 26, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at