rs104894679

Variant names:

• chr19-46756376-A-G
• rs104894679
• NM_024301.5:c.926A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_024301.5(FKRP):​c.926A>G​(p.Tyr309Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,411,472 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y309Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 6.67

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

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.8498 (below the threshold of 3.09). Trascript score misZ: -2.4986 (below the threshold of 3.09). GenCC associations: The gene is linked to muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy, type A, congenital muscular dystrophy without intellectual disability, muscular dystrophy-dystroglycanopathy type B5, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 19-46756376-A-G is Pathogenic according to our data. Variant chr19-46756376-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46756376-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.926A>G	p.Tyr309Cys	missense_variant	Exon 4 of 4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.926A>G	p.Tyr309Cys	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4
FKRP	ENST00000391909.7	c.926A>G	p.Tyr309Cys	missense_variant	Exon 4 of 4	2		ENSP00000375776.2
FKRP	ENST00000597339.5	n.247-5457A>G		intron_variant	Intron 3 of 3	5
FKRP	ENST00000600646.5	n.247+7711A>G		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000628 AC: 1 AN: 159312 AF XY: 0.0000115

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000496 AC: 7 AN: 1411472 Hom.: 0 Cov.: 32 AF XY: 0.00000717 AC XY: 5 AN XY: 697784

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32584

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 36966

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25184

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37156

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 80458

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 47058

Gnomad4 NFE exome AF: 0.00000551 AC: 6 AN: 1087978

Gnomad4 Remaining exome AF: 0.0000171 AC: 1 AN: 58534

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 Pathogenic:1

Jul 10, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 5 Pathogenic:1

Dec 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Aug 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects FKRP function (PMID: 31268217). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FKRP protein function. ClinVar contains an entry for this variant (Variation ID: 4218). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 11071142, 11592034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894679, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 309 of the FKRP protein (p.Tyr309Cys). -

not provided Uncertain:1

Oct 21, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.85		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.99
MPC		1.8
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.85
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs104894679; hg19: chr19-47259633;