rs587777223

chr19-46755451-A-Cchr19-46755451-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_024301.5(FKRP):c.1A>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000138 in 1,452,622 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FKRP NM_024301.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.61

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_024301.5 (FKRP) was described as [Pathogenic] in ClinVar as 120180
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-46755451-A-C is Pathogenic according to our data. Variant chr19-46755451-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1072163.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.1A>C	p.Met1?	start_lost	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.1A>C	p.Met1?	start_lost	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452622 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722732

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the FKRP mRNA. The next in-frame methionine is located at codon 144. Disruption of the initiator codon has been observed in individuals with Walker-Warburg syndrome or limb-girdle muscular dystrophy (PMID: 12666124, 20236121). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro89 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16368217, 17446099, 18639457, 18691338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1072163). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Benign	21
Dann	Benign	0.91
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		0.61	.;P;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.59, 0.72
MutPred		1.0		Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);
MVP		0.92
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-47258708;