rs148206382

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024301.5(FKRP):c.427C>A(p.Arg143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,493,634 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 30 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.56

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]

FKRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009333223).

BP6

Variant 19-46755877-C-A is Benign according to our data. Variant chr19-46755877-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 129057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46755877-C-A is described in Lovd as [Pathogenic]. Variant chr19-46755877-C-A is described in Lovd as [Likely_benign]. Variant chr19-46755877-C-A is described in Lovd as [Benign]. Variant chr19-46755877-C-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00362 (551/152318) while in subpopulation NFE AF= 0.00609 (414/68012). AF 95% confidence interval is 0.0056. There are 1 homozygotes in gnomad4. There are 250 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.427C>A	p.Arg143Ser	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.427C>A	p.Arg143Ser	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

552

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00448

AC:

445

AN:

99432

Hom.:

AF XY:

0.00418

AC XY:

227

AN XY:

54344

show subpopulations

Gnomad AFR exome

AF:

0.000893

Gnomad AMR exome

AF:

0.00501

Gnomad ASJ exome

AF:

0.00342

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00363

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00661

Gnomad OTH exome

AF:

0.00730

GnomAD4 exome

AF:

0.00542

AC:

7272

AN:

1341316

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

3552

AN XY:

657222

show subpopulations

Gnomad4 AFR exome

AF:

0.000995

Gnomad4 AMR exome

AF:

0.00535

Gnomad4 ASJ exome

AF:

0.00278

Gnomad4 EAS exome

AF:

0.0000286

Gnomad4 SAS exome

AF:

0.00478

Gnomad4 FIN exome

AF:

0.000336

Gnomad4 NFE exome

AF:

0.00597

Gnomad4 OTH exome

AF:

0.00551

GnomAD4 genome

AF:

0.00362

AC:

551

AN:

152318

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

250

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00434

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00609

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00450

Hom.:

Bravo

AF:

0.00405

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00106

AC:

ESP6500EA

AF:

0.00491

AC:

ExAC

AF:

0.00190

AC:

177

Asia WGS

AF:

0.000868

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 30, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2024	Variant summary: FKRP c.427C>A (p.Arg143Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 1493634 control chromosomes in the gnomAD database (v4.0.0), including 31 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FKRP causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0024), strongly suggesting that the variant is benign. c.427C>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Sframeli_2017, Brockington_2001). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28688748, 11741828). ClinVar contains an entry for this variant (Variation ID: 129057). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2014	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FKRP: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2019	This variant is associated with the following publications: (PMID: 11741828, 16344347, 22451200, 16717227, 18832576, 27884173, 29065428, 28482373, 32403337) -

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;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 13, 2022

- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 14, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Walker-Warburg congenital muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Pathogenic

0.17

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.66

T;.;T

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Pathogenic

0.87

MutationTaster

Benign

0.98

D;D

PrimateAI

Pathogenic

0.80

Sift4G

Benign

0.085

T;T;T

Polyphen

0.18

.;B;B

Vest4

0.58, 0.58

MVP

0.98

MPC

0.83

ClinPred

0.0045

GERP RS

3.6

Varity_R

0.59

gMVP

0.79

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