rs104894683
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_024301.5(FKRP):c.235G>A(p.Val79Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,590,552 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V79A) has been classified as Uncertain significance.
Frequency
Consequence
NM_024301.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.235G>A | p.Val79Met | missense_variant | 4/4 | ENST00000318584.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.235G>A | p.Val79Met | missense_variant | 4/4 | 1 | NM_024301.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00394 AC: 600AN: 152200Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00103 AC: 222AN: 215090Hom.: 1 AF XY: 0.000872 AC XY: 103AN XY: 118136
GnomAD4 exome AF: 0.000429 AC: 617AN: 1438234Hom.: 0 Cov.: 33 AF XY: 0.000370 AC XY: 265AN XY: 715266
GnomAD4 genome AF: 0.00398 AC: 606AN: 152318Hom.: 3 Cov.: 33 AF XY: 0.00389 AC XY: 290AN XY: 74492
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:4
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 12, 2024 | Variant summary: FKRP c.235G>A (p.Val79Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 1590552 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. ClinVar contains an entry for this variant (Variation ID: 4229). Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 31, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 23, 2018 | The FKRP c.235G>A; p.Val79Met variant (rs104894683) is reported in several individuals affected with limb girdle muscular dystrophy (de Paula 2003), including three siblings that carried the p.Val79Met variant in trans to a nonsense variant (Vieira 2006). Of the three siblings, two were severely affected and also carried a p.Pro89Ala variant, which was not identified in the third mildly affected sibling (Vieira 2006). The p.Val79Met variant is reported in ClinVar (Variation ID: 4229) and is found in the African population with an overall allele frequency of 1.5% (320/21382 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 79 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val79Met variant is uncertain at this time. References: de Paula F et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003 Dec;11(12):923-30. Vieira NM et al. Mutation analysis in the FKRP gene provides an explanation for a rare cause of intrafamilial clinical variability in LGMD2I. Neuromuscul Disord. 2006 Dec;16(12):870-3. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2020 | This variant is associated with the following publications: (PMID: 22995991, 18645206, 17113772, 14647208, 25898921) - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 03, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:1Benign:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2003 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Walker-Warburg congenital muscular dystrophy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at