rs752243337
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_024301.5(FKRP):āc.1418T>Gā(p.Phe473Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F473F) has been classified as Likely benign.
Frequency
Consequence
NM_024301.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.1418T>G | p.Phe473Cys | missense_variant | Exon 4 of 4 | ENST00000318584.10 | NP_077277.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.1418T>G | p.Phe473Cys | missense_variant | Exon 4 of 4 | 1 | NM_024301.5 | ENSP00000326570.4 | ||
FKRP | ENST00000391909.7 | c.1418T>G | p.Phe473Cys | missense_variant | Exon 4 of 4 | 2 | ENSP00000375776.2 | |||
FKRP | ENST00000597339.5 | n.247-4965T>G | intron_variant | Intron 3 of 3 | 5 | |||||
FKRP | ENST00000600646.5 | n.247+8203T>G | intron_variant | Intron 3 of 3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000825 AC: 2AN: 242340Hom.: 0 AF XY: 0.00000755 AC XY: 1AN XY: 132466
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458966Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725580
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2I;C1847759:Muscular dystrophy-dystroglycanopathy type B5;C3150413:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1
The p.Phe473Cys variant in the FKRP gene has been previously reported in the compound heterozygous state with a frameshift variant in an individual with congenital-onset muscular dystrophy with eye and brain anomalies (Kava et al., 2013). While phase of these variants was not reported, functional studies in induced pluripotent stem cells generated from this affected individual demonstrated impaired alpha-DG functional glycosylation (Ortiz-Cordero et al., 2021). This variant has been identified in 2/242,340 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the C-terminal catalytic domain of the FKRP protein (Ortiz-Cordero et al., 2021). Other nearby pathogenic and likely pathogenic variants have been described in this domain (p.Asn463Asp, p.Asn463Ile, p.Tyr465Ser, p.Ile478Thr). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Phe473Cys variant as likely pathogenic for FKRP-related muscular dystrophy-dystroglycanopathy in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PM2; PM3; PM1_Supporting; PP3] -
Autosomal recessive limb-girdle muscular dystrophy type 2I Uncertain:1
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Walker-Warburg congenital muscular dystrophy Uncertain:1
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 473 of the FKRP protein (p.Phe473Cys). This variant is present in population databases (rs752243337, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 24139536). ClinVar contains an entry for this variant (Variation ID: 550064). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at