rs768376273

Variant names:

• chr19-46755487-G-A
• rs768376273
• NM_024301.5:c.37G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-46755487-G-A
• chr19-46755487-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FKRP NM_024301.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.20
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy type 2I

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics
• muscular dystrophy-dystroglycanopathy type B5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• myopathy caused by variation in FKRP

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital muscular dystrophy with cerebellar involvement

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy with intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital muscular dystrophy without intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscle-eye-brain disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 autosomal recessive limb-girdle muscular dystrophy type 2I, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5, congenital muscular dystrophy with intellectual disability, muscular dystrophy-dystroglycanopathy, type A, muscle-eye-brain disease, congenital muscular dystrophy with cerebellar involvement, myopathy caused by variation in FKRP, muscular dystrophy-dystroglycanopathy type B5, congenital muscular dystrophy without intellectual disability.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKRP	NM_024301.5	c.37G>A	p.Ala13Thr	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.37G>A	p.Ala13Thr	missense_variant	Exon 4 of 4	1	NM_024301.5	ENSP00000326570.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 240058 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1457344 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725026

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.0000224 AC: 1 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111230

Other (OTH) AF: 0.0000166 AC: 1 AN: 60200

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

May 02, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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

Aug 29, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
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	D
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	D
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	D
MutationAssessor	Benign	1.7	.;L;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.77	T
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	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.16
gMVP		0.68
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

dbSNP: rs768376273; hg19: chr19-47258744;