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rs754403441

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024301.5(FKRP):​c.1141del​(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 𝑓: 0.0000014 ( 0 hom. )

Consequence

FKRP
NM_024301.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.60
Variant links:
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
?
    PVS1 - null variant (nonsense, frameshift, canonical Β±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
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
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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
FKRPNM_024301.5 linkuse as main transcriptc.1141del p.Ala381GlnfsTer47 frameshift_variant 4/4 ENST00000318584.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FKRPENST00000318584.10 linkuse as main transcriptc.1141del p.Ala381GlnfsTer47 frameshift_variant 4/41 NM_024301.5 P1
FKRPENST00000391909.7 linkuse as main transcriptc.1141del p.Ala381GlnfsTer47 frameshift_variant 4/42 P1
FKRPENST00000597339.5 linkuse as main transcriptn.247-5242del intron_variant, non_coding_transcript_variant 5
FKRPENST00000600646.5 linkuse as main transcriptn.247+7926del intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458012
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
725080
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
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 submitterclinical testingEurofins Ntd Llc (ga)Jul 11, 2016- -
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 06, 2024This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754403441; hg19: chr19-47259842; API