rs104894683

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024301.5(FKRP):c.235G>A(p.Val79Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,590,552 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:11

Conservation

PhyloP100: 1.83

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017470866).

BP6

Variant 19-46755685-G-A is Benign according to our data. Variant chr19-46755685-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4229.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=4}. Variant chr19-46755685-G-A is described in Lovd as [Pathogenic]. Variant chr19-46755685-G-A is described in Lovd as [Likely_benign]. Variant chr19-46755685-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00398 (606/152318) while in subpopulation AFR AF= 0.0139 (578/41584). AF 95% confidence interval is 0.013. There are 3 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 link	c.235G>A	p.Val79Met	missense_variant	4/4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10 link	c.235G>A	p.Val79Met	missense_variant	4/4	1	NM_024301.5	ENSP00000326570.4		Q9H9S5

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

600

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00103

AC:

222

AN:

215090

Hom.:

AF XY:

0.000872

AC XY:

103

AN XY:

118136

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000510

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000705

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000205

Gnomad OTH exome

AF:

0.000364

GnomAD4 exome

AF:

0.000429

AC:

617

AN:

1438234

Hom.:

Cov.:

AF XY:

0.000370

AC XY:

265

AN XY:

715266

show subpopulations

Gnomad4 AFR exome

AF:

0.0153

Gnomad4 AMR exome

AF:

0.000567

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000710

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00105

GnomAD4 genome

AF:

0.00398

AC:

606

AN:

152318

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

290

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0139

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000810

Hom.:

Bravo

AF:

0.00438

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00117

AC:

141

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2024	Variant summary: FKRP c.235G>A (p.Val79Met) results in a 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 0.00077 in 1590552 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 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 a benign polymorphism found primarily in populations of African or African-American origin. ClinVar contains an entry for this variant (Variation ID: 4229). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2018	The FKRP c.235G>A; p.Val79Met variant (rs104894683) is reported in several individuals affected with limb girdle muscular dystrophy (de Paula 2003), including three siblings that carried the p.Val79Met variant in trans to a nonsense variant (Vieira 2006). Of the three siblings, two were severely affected and also carried a p.Pro89Ala variant, which was not identified in the third mildly affected sibling (Vieira 2006). The p.Val79Met variant is reported in ClinVar (Variation ID: 4229) and is found in the African population with an overall allele frequency of 1.5% (320/21382 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 79 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val79Met variant is uncertain at this time. References: de Paula F et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003 Dec;11(12):923-30. Vieira NM et al. Mutation analysis in the FKRP gene provides an explanation for a rare cause of intrafamilial clinical variability in LGMD2I. Neuromuscul Disord. 2006 Dec;16(12):870-3. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 31, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	This variant is associated with the following publications: (PMID: 22995991, 18645206, 17113772, 14647208, 25898921) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2003	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.42

.;T;.;T;.;.;.;.;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.82

T;.;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.017

T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

1.1

.;L;.;L;.;.;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.5

.;N;.;N;.;.;.;.;.;.

REVEL

Uncertain

0.43

Sift

Uncertain

0.011

.;D;.;D;.;.;.;.;.;.

Sift4G

Uncertain

0.057

T;D;D;D;D;D;D;D;D;D

Polyphen

0.89

.;P;.;P;.;.;.;.;.;.

Vest4

0.68, 0.77

MVP

0.63

MPC

1.0

ClinPred

0.010

GERP RS

2.6

Varity_R

0.17

gMVP

0.67

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