rs1555738797

Positions:

• chr19-46756286-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_024301.5(FKRP):​c.836G>C​(p.Trp279Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W279R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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 3 ACMG points.

• PM1: In a hotspot region, there are 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.29498854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5	c.836G>C	p.Trp279Ser	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10	c.836G>C	p.Trp279Ser	missense_variant	4/4	1	NM_024301.5	P1
FKRP	ENST00000391909.7	c.836G>C	p.Trp279Ser	missense_variant	4/4	2		P1
FKRP	ENST00000597339.5	n.247-5547G>C		intron_variant, non_coding_transcript_variant		5
FKRP	ENST00000600646.5	n.247+7621G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Walker-Warburg congenital muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has not been reported in the literature in individuals with FKRP-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces tryptophan with serine at codon 279 of the FKRP protein (p.Trp279Ser). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.36	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.45	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.089	B;B
Vest4		0.27
MutPred		0.63		Gain of disorder (P = 0.0057);Gain of disorder (P = 0.0057);
MVP		0.82
MPC		1.0
ClinPred		0.34	T
GERP RS		4.2
Varity_R		0.41
gMVP		0.87

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: rs1555738797; hg19: chr19-47259543;