rs768376273
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_024301.5(FKRP):c.37G>A(p.Ala13Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000618 in 1,457,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13S) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
FKRP
NM_024301.5 missense
NM_024301.5 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 6.20
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-46755487-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FKRP | NM_024301.5 | c.37G>A | p.Ala13Thr | missense_variant | 4/4 | ENST00000318584.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FKRP | ENST00000318584.10 | c.37G>A | p.Ala13Thr | missense_variant | 4/4 | 1 | NM_024301.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000417 AC: 1AN: 240058Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131512
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GnomAD4 exome AF: 0.00000618 AC: 9AN: 1457344Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3AN XY: 725026
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GnomAD4 genome Cov.: 33
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33
ExAC
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2I Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 02, 2017 | Our patient had testing at the Invitae laboratory. Given the lack of case data, the fact that this is a heterozygous variant in a gene associated with autosomal recessive disease, and overall lack of gene-phenotype association, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The FKRP gene is associated with autosomal recessive muscular dystrophy and DCM. Our patient has only one heterozygous variant, and a phenotype of Afib. The variant has not been reported in any cases of FKRP-related disease. The variant is present in 1 individual listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant was observed in 1 of 16,627 individuals of Latino descent (MAF = 0.003%). The average coverage at that site in gnomAD is 30x. It should be noted that this variant is filtered out due to quality filters on first pass. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2019 | The p.A13T variant (also known as c.37G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 37. The alanine at codon 13 is replaced by threonine, an amino acid with similar properties. An alternate amino acid substitution at this codon, p.A13S (c.37G>T) has been reported in an individual with myopathy, who also had an additional FKRP variant detected; however, clinical details were limited (Dai Y et al. Neuromuscul. Disord., 2015 Aug;25:617-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Walker-Warburg congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces alanine with threonine at codon 13 of the FKRP protein (p.Ala13Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs768376273, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. 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: "Tolerated"; 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;T
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;L;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
Sift
Benign
.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;T;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.
Vest4
0.63, 0.65
MutPred
Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);
MVP
MPC
1.6
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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