rs104894680

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024301.5(FKRP):c.1154C>A(p.Ser385*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000118 in 1,611,280 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FKRP
NM_024301.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.87

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:

FKRP (HGNC:):

FKRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-46756604-C-A is Pathogenic according to our data. Variant chr19-46756604-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756604-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.1154C>A	p.Ser385*	stop_gained	4/4	ENST00000318584.10	NP_077277.1	Q9H9S5A0A024R0R7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.1154C>A	p.Ser385*	stop_gained	4/4	1	NM_024301.5	ENSP00000326570.4	Q9H9S5
FKRP	ENST00000391909.7 linkuse as main transcript	c.1154C>A	p.Ser385*	stop_gained	4/4	2		ENSP00000375776.2	Q9H9S5
FKRP	ENST00000597339.5 linkuse as main transcript	n.247-5229C>A		intron_variant		5
FKRP	ENST00000600646.5 linkuse as main transcript	n.247+7939C>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242048

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1459128

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725758

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 21, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 29, 2021

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 12, 2023

- -

Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2023

The p.S385* pathogenic mutation (also known as c.1154C>A), located in coding exon 1 of the FKRP gene, results from a C to A substitution at nucleotide position 1154. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration occurs at the 3' terminus of theFKRP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 111 amino acids (22%) of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This mutation has been detected in the compound heterozygous state with other FKRP variants in individuals with congenital and limb-girdle muscular dystrophies (Brockington M et al. Am J Hum Genet. 2001 Dec;69(6):1198-209; Poppe M et al. Neurology. 2003 Apr;60(8):1246-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Walker-Warburg congenital muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2023

This sequence change creates a premature translational stop signal (p.Ser385*) in the FKRP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 111 amino acid(s) of the FKRP protein. 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 premature translational stop signal has been observed in individuals with congenital muscular dystrophy and limb girdle muscular dystrophy (PMID: 11592034, 12666124, 12707425, 14742276). This variant is also known as Ser384*. ClinVar contains an entry for this variant (Variation ID: 4219). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.95

Vest4

0.55

GERP RS

5.0

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