rs752243337

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_024301.5(FKRP):​c.1418T>G​(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

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.75
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_024301.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
Variant 19-46756868-T-G is Pathogenic according to our data. Variant chr19-46756868-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550064.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FKRPNM_024301.5 linkc.1418T>G p.Phe473Cys missense_variant Exon 4 of 4 ENST00000318584.10 NP_077277.1 Q9H9S5A0A024R0R7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FKRPENST00000318584.10 linkc.1418T>G p.Phe473Cys missense_variant Exon 4 of 4 1 NM_024301.5 ENSP00000326570.4 Q9H9S5
FKRPENST00000391909.7 linkc.1418T>G p.Phe473Cys missense_variant Exon 4 of 4 2 ENSP00000375776.2 Q9H9S5
FKRPENST00000597339.5 linkn.247-4965T>G intron_variant Intron 3 of 3 5
FKRPENST00000600646.5 linkn.247+8203T>G intron_variant Intron 3 of 3 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000825
AC:
2
AN:
242340
Hom.:
0
AF XY:
0.00000755
AC XY:
1
AN XY:
132466
show subpopulations
Gnomad AFR exome
AF:
0.000137
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458966
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
725580
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

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
Oct 20, 2021
Clinical Genomics Laboratory, Stanford Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 06, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Walker-Warburg congenital muscular dystrophy Uncertain:1
Jun 08, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.2
M;M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.1
D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.76
Gain of methylation at K472 (P = 0.0333);Gain of methylation at K472 (P = 0.0333);
MVP
0.98
MPC
2.0
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.81
gMVP
0.91

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: rs752243337; hg19: chr19-47260125; API