rs777292177
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000228.3(LAMB3):βc.3024delβ(p.Arg1009GlyfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.000020 ( 0 hom. )
Consequence
LAMB3
NM_000228.3 frameshift
NM_000228.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.87
Genes affected
LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-209617933-GA-G is Pathogenic according to our data. Variant chr1-209617933-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMB3 | NM_000228.3 | c.3024del | p.Arg1009GlyfsTer21 | frameshift_variant | 20/23 | ENST00000356082.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMB3 | ENST00000356082.9 | c.3024del | p.Arg1009GlyfsTer21 | frameshift_variant | 20/23 | 1 | NM_000228.3 | P1 | |
LAMB3 | ENST00000367030.7 | c.3024del | p.Arg1009GlyfsTer21 | frameshift_variant | 20/23 | 1 | P1 | ||
LAMB3 | ENST00000391911.5 | c.3024del | p.Arg1009GlyfsTer21 | frameshift_variant | 19/22 | 1 | P1 | ||
LAMB3 | ENST00000455193.1 | c.231del | p.Arg78GlyfsTer21 | frameshift_variant | 2/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251478Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135918
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GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727248
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74364
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 15, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). This variant has been observed in individual(s) with epidermolysis bullosa (PMID: 11023379). ClinVar contains an entry for this variant (Variation ID: 370321). This variant is present in population databases (rs777292177, ExAC 0.03%). This sequence change creates a premature translational stop signal (p.Arg1009Glyfs*21) in the LAMB3 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at