rs1555738521

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_024301.5(FKRP):​c.539C>A​(p.Ala180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

FKRP
NM_024301.5 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a strand (size 5) in uniprot entity FKRP_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_024301.5
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FKRPNM_024301.5 linkc.539C>A p.Ala180Asp missense_variant 4/4 ENST00000318584.10 NP_077277.1 Q9H9S5A0A024R0R7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FKRPENST00000318584.10 linkc.539C>A p.Ala180Asp missense_variant 4/41 NM_024301.5 ENSP00000326570.4 Q9H9S5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 22, 2017This sequence change replaces alanine with aspartic acid at codon 180 of the FKRP protein (p.Ala180Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FKRP-related disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;D
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.79
.;T
M_CAP
Pathogenic
0.69
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.1
L;L
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-2.7
D;D
REVEL
Uncertain
0.57
Sift
Benign
0.070
T;T
Sift4G
Uncertain
0.024
D;D
Polyphen
0.0070
B;B
Vest4
0.82
MutPred
0.29
Loss of MoRF binding (P = 0.0452);Loss of MoRF binding (P = 0.0452);
MVP
0.98
MPC
1.9
ClinPred
0.97
D
GERP RS
3.5
Varity_R
0.84
gMVP
0.96

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: rs1555738521; hg19: chr19-47259246; API