rs754403441
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024301.5(FKRP):βc.1141delβ(p.Ala381GlnfsTer47) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,458,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. R379R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
FKRP
NM_024301.5 frameshift
NM_024301.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.60
Genes affected
FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-46756585-CG-C is Pathogenic according to our data. Variant chr19-46756585-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 289250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756585-CG-C is described in Lovd as [Pathogenic]. Variant chr19-46756585-CG-C is described in Lovd as [Likely_pathogenic]. Variant chr19-46756585-CG-C is described in Lovd as [Pathogenic]. Variant chr19-46756585-CG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.1141del | p.Ala381GlnfsTer47 | frameshift_variant | 4/4 | ENST00000318584.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.1141del | p.Ala381GlnfsTer47 | frameshift_variant | 4/4 | 1 | NM_024301.5 | P1 | |
FKRP | ENST00000391909.7 | c.1141del | p.Ala381GlnfsTer47 | frameshift_variant | 4/4 | 2 | P1 | ||
FKRP | ENST00000597339.5 | n.247-5242del | intron_variant, non_coding_transcript_variant | 5 | |||||
FKRP | ENST00000600646.5 | n.247+7926del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458012Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725080
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32
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725080
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 11, 2016 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change creates a premature translational stop signal (p.Ala381Glnfs*47) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the FKRP protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 17994539). This variant is also known as Arg379ArgfsX10. ClinVar contains an entry for this variant (Variation ID: 289250). This variant disrupts a region of the FKRP protein in which other variant(s) (p.Ile478Thr) have been determined to be pathogenic (PMID: 16476814, 18639457, 19299310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
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