rs773024545

chr19-46755619-G-Achr19-46755619-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_024301.5(FKRP):c.169G>A(p.Glu57Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,774 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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 5.41

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 6 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, 9 uncertain in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 19-46755619-G-A is Pathogenic according to our data. Variant chr19-46755619-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283305.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.169G>A	p.Glu57Lys	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.169G>A	p.Glu57Lys	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000864 AC: 2 AN: 231428 Hom.: 0 AF XY: 0.00000791 AC XY: 1 AN XY: 126364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

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: 0.00000954

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451774 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 02, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2016	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 05, 2017	- -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 57 of the FKRP protein (p.Glu57Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 30564623, 32351701, 34509255). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 283305). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.58, 0.56
MutPred		0.34		Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);Gain of methylation at E57 (P = 0.0097);
MVP		1.0
MPC		1.7
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.47
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

Other links and lift over

dbSNP: rs773024545; hg19: chr19-47258876;