rs775278003
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5
The NM_000426.4(LAMA2):c.3556-13T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000426.4 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.3556-13T>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000421865.3 | |||
LAMA2 | NM_001079823.2 | c.3556-13T>A | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.3556-13T>A | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000426.4 | ||||
LAMA2 | ENST00000617695.5 | c.3556-13T>A | splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
LAMA2 | ENST00000618192.5 | c.3820-13T>A | splice_polypyrimidine_tract_variant, intron_variant | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251408Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461268Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727016
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
Merosin deficient congenital muscular dystrophy Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 27, 2018 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported to affect splicing of LAMA2 [PMID 24611677] - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 12, 2017 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change falls in intron 24 of the LAMA2 gene. It does not directly change the encoded amino acid sequence of the LAMA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs775278003, gnomAD 0.03%). This variant has been observed in individual(s) with congenital muscular dystrophy (PMID: 24611677). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555549). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 24611677). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at