chr19-46755487-G-A

Position:

chr19-46755487-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_024301.5(FKRP):c.37G>A(p.Ala13Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000618 in 1,457,344 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A13S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-46755487-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.37G>A	p.Ala13Thr	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000417

AC:

AN:

240058

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131512

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1457344

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2I

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 02, 2017

Our patient had testing at the Invitae laboratory. Given the lack of case data, the fact that this is a heterozygous variant in a gene associated with autosomal recessive disease, and overall lack of gene-phenotype association, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The FKRP gene is associated with autosomal recessive muscular dystrophy and DCM. Our patient has only one heterozygous variant, and a phenotype of Afib. The variant has not been reported in any cases of FKRP-related disease. The variant is present in 1 individual listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant was observed in 1 of 16,627 individuals of Latino descent (MAF = 0.003%). The average coverage at that site in gnomAD is 30x. It should be noted that this variant is filtered out due to quality filters on first pass. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2019

The p.A13T variant (also known as c.37G>A), located in coding exon 1 of the FKRP gene, results from a G to A substitution at nucleotide position 37. The alanine at codon 13 is replaced by threonine, an amino acid with similar properties. An alternate amino acid substitution at this codon, p.A13S (c.37G>T) has been reported in an individual with myopathy, who also had an additional FKRP variant detected; however, clinical details were limited (Dai Y et al. Neuromuscul. Disord., 2015 Aug;25:617-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Walker-Warburg congenital muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces alanine with threonine at codon 13 of the FKRP protein (p.Ala13Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs768376273, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;T

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;.;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.69

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

.;L;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.95

.;N;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.64

Sift

Benign

0.15

.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;T;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.

Vest4

0.63, 0.65

MutPred

0.33

Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);Loss of MoRF binding (P = 0.2163);

MVP

0.98

MPC

1.6

ClinPred

0.88

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.16

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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