rs747785577

chr19-46756813-G-Achr19-46756813-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_024301.5(FKRP):c.1363G>A(p.Ala455Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A455S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-46756814-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 19-46756813-G-A is Pathogenic according to our data. Variant chr19-46756813-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 501628.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.1363G>A	p.Ala455Thr	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.1363G>A	p.Ala455Thr	missense_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7	c.1363G>A	p.Ala455Thr	missense_variant	4/4	2		P1
FKRP	ENST00000597339.5	n.247-5020G>A		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+8148G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447538 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719168

Gnomad4 AFR exome AF: 0.00

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2022

This variant has not been reported in the literature in individuals affected with FKRP-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala455 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14652796, 16368217, 18671187, 23420653, 23894383). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 501628). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 455 of the FKRP protein (p.Ala455Thr). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.10	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.40	B;B
Vest4		0.33
MutPred		0.50		Gain of relative solvent accessibility (P = 0.0483);Gain of relative solvent accessibility (P = 0.0483);
MVP		0.99
MPC		0.73
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.32
gMVP		0.63

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

Other links and lift over

dbSNP: rs747785577; hg19: chr19-47260070;