rs104894683

chr19-46755685-G-Achr19-46755685-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V79A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:10
• Conservation: PhyloP100: 1.83

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 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: {Likely_benign=4, Uncertain_significance=1, Benign=3}. 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 GnomAd at 3 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.235G>A	p.Val79Met	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152200 Hom.: 3 Cov.: 33

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.: 1 AF XY: 0.000872 AC XY: 103 AN XY: 118136

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.: 0 Cov.: 33 AF XY: 0.000370 AC XY: 265 AN XY: 715266

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.: 3 Cov.: 33 AF XY: 0.00389 AC XY: 290 AN XY: 74492

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.: 0

Bravo AF: 0.00438

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 141

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 31, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2024	Variant summary: IDUA c.235G>A (p.Ala79Thr) 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 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.235G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1. These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign. -

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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2I Pathogenic:1 Benign: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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.37	N
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	D
MutationTaster	Benign	0.13	A;A
PrimateAI	Uncertain	0.65	T
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	T
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

Other links and lift over

dbSNP: rs104894683; hg19: chr19-47258942;