rs886043458

Positions:

• chr19-46756431-CTAT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_024301.5(FKRP):​c.982_984del​(p.Tyr328del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000132 in 152,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: FKRP NM_024301.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 20) in uniprot entity FKRP_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_024301.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_024301.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKRP	NM_024301.5	c.982_984del	p.Tyr328del	inframe_deletion	4/4	ENST00000318584.10	NP_077277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKRP	ENST00000318584.10	c.982_984del	p.Tyr328del	inframe_deletion	4/4	1	NM_024301.5	ENSP00000326570	P1
FKRP	ENST00000391909.7	c.982_984del	p.Tyr328del	inframe_deletion	4/4	2		ENSP00000375776	P1
FKRP	ENST00000597339.5	n.247-5401_247-5399del		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7767_247+7769del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152044 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

Gnomad4 AFR AF: 0.0000241

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: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2016	- -

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 02, 2021

- -

Walker-Warburg congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

This variant, c.982_984del, results in the deletion of 1 amino acid(s) of the FKRP protein (p.Tyr328del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 286718). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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: rs886043458; hg19: chr19-47259688;