rs587780334

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BP4_Strong

The NM_024301.5(FKRP):c.1027G>C(p.Glu343Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 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. E343K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.58

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]

FKRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_024301.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46756477-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.012301803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.1027G>C	p.Glu343Gln	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FKRP	ENST00000318584.10 linkuse as main transcript	c.1027G>C	p.Glu343Gln	missense_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7 linkuse as main transcript	c.1027G>C	p.Glu343Gln	missense_variant	4/4	2		P1
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5356G>C		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7812G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150608

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000105

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00841

AC:

930

AN:

110648

Hom.:

AF XY:

0.00903

AC XY:

522

AN XY:

57816

show subpopulations

Gnomad AFR exome

AF:

0.00637

Gnomad AMR exome

AF:

0.000904

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.000951

Gnomad SAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.0384

Gnomad NFE exome

AF:

0.00931

Gnomad OTH exome

AF:

0.00536

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00117

AC:

1597

AN:

1366768

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

899

AN XY:

670116

show subpopulations

Gnomad4 AFR exome

AF:

0.000829

Gnomad4 AMR exome

AF:

0.000987

Gnomad4 ASJ exome

AF:

0.00382

Gnomad4 EAS exome

AF:

0.0000843

Gnomad4 SAS exome

AF:

0.00378

Gnomad4 FIN exome

AF:

0.0105

Gnomad4 NFE exome

AF:

0.000384

Gnomad4 OTH exome

AF:

0.00112

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000664

AC:

AN:

150684

Hom.:

Cov.:

AF XY:

0.0000953

AC XY:

AN XY:

73468

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000105

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00272

Hom.:

ExAC

AF:

0.00847

AC:

698

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 06, 2014

- -

Walker-Warburg congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

1.0

MetaRNN

Benign

0.012

T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.53

MVP

0.94

MPC

1.6

ClinPred

0.046

GERP RS

4.4

Varity_R

0.93

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over