rs119463995
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001079802.2(FKTN):c.340G>A(p.Ala114Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,890 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
FKTN
NM_001079802.2 missense
NM_001079802.2 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 8.09
Genes affected
FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
Variant 9-105601319-G-A is Pathogenic according to our data. Variant chr9-105601319-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3213.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr9-105601319-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FKTN | NM_001079802.2 | c.340G>A | p.Ala114Thr | missense_variant | 5/11 | ENST00000357998.10 | NP_001073270.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FKTN | ENST00000357998.10 | c.340G>A | p.Ala114Thr | missense_variant | 5/11 | 5 | NM_001079802.2 | ENSP00000350687.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1454890Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 724110
GnomAD4 exome
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2
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1454890
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29
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2
AN XY:
724110
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2M Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 01, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FKTN protein function. ClinVar contains an entry for this variant (Variation ID: 3213). This missense change has been observed in individual(s) with FKTN-related conditions (PMID: 17878207, 19342235). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the FKTN protein (p.Ala114Thr). - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 09, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;D;N
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
D;D;.;.
Vest4
MutPred
Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP
MPC
0.31
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at