2-69354314-T-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001244710.2(GFPT1):c.686-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000113 in 1,589,450 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001244710.2 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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GFPT1 | NM_001244710.2 | c.686-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 19 | ENST00000357308.9 | NP_001231639.1 | ||
GFPT1 | NM_002056.4 | c.685+175A>G | intron_variant | Intron 8 of 18 | NP_002047.2 | |||
GFPT1 | XM_017003801.2 | c.761-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 19 | XP_016859290.1 | |||
GFPT1 | XM_017003802.3 | c.760+175A>G | intron_variant | Intron 8 of 18 | XP_016859291.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GFPT1 | ENST00000357308.9 | c.686-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 19 | 5 | NM_001244710.2 | ENSP00000349860.4 | |||
GFPT1 | ENST00000361060.5 | c.685+175A>G | intron_variant | Intron 8 of 18 | 1 | ENSP00000354347.4 | ||||
GFPT1 | ENST00000674507.1 | c.685+175A>G | intron_variant | Intron 8 of 17 | ENSP00000501332.1 | |||||
GFPT1 | ENST00000674438.1 | c.469+175A>G | intron_variant | Intron 6 of 16 | ENSP00000501469.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000227 AC: 5AN: 219992Hom.: 0 AF XY: 0.0000332 AC XY: 4AN XY: 120432
GnomAD4 exome AF: 0.0000104 AC: 15AN: 1437246Hom.: 0 Cov.: 28 AF XY: 0.0000126 AC XY: 9AN XY: 714752
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74354
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 12 Pathogenic:5
This sequence change affects an acceptor splice site in intron 8 of the GFPT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with congenital myasthenic syndrome (PMID: 23794683, 28464723, 29054425). ClinVar contains an entry for this variant (Variation ID: 540353). Studies have shown that disruption of this splice site results in deletion of the first 4 nucleotides of the muscle-specific exon of GFPT1, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23794683). For these reasons, this variant has been classified as Pathogenic. -
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Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000540353). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:23794683, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
The homozygous c.686-2A>G variant in GFPT1 was identified by our study in one individual with congenital myasthenic syndrome. The c.686-2A>G variant in GFPT1 has been previously reported in at least four unrelated individuals with congenital myasthenic syndrome 12 (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171, PMID: 23794683) but has been identified in 0.015% (5/33776) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772941684). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 540353) and has been interpreted as pathogenic by Invitae, Illumina, 3billion, Pars Genome Lab, and Kariminejad - Najmabadi Pathology & Genetics Center. Of these four individuals with congenital myasthenic syndrome 12 (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171, PMID: 23794683), three were homozygotes (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171) and one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 23794683, ClinVar Variation ID: 859066), which increases the likelihood that the c.686-2A>G variant is pathogenic. RT-PCR and cDNA analysis of patient muscle tissue showed that the c.686-2A>G variant resulted in a 4 base-pair deletion of the muscle-specific exon of GFPT1, leading to frameshift and a premature stop codon 56 amino acids downstream (PMID: 23794683). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the GFPT1 gene is strongly associated to autosomal recessive congenital myasthenic syndrome 12. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myasthenic syndrome 12. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PS3_Supporting (Richards 2015). -
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GFPT1-related myasthenic syndrome Pathogenic:1
The GFPT1 c.686-2A>G variant results in the substitution of an adenine within the consensus splice acceptor site with a guanine, which may result in splicing defects. Across a selection of the available literature, this variant has been identified in at least five individuals with a congenital myasthenic syndrome or limb-girdle muscle weakness, including in a confirmed or presumed homozygous state in four individuals, and in a compound heterozygous state in one individual (Selcen et al. 2013; Yiş et al. 2017; Natera-de Benito et al. 2017; Gonzalez-Quereda et al. 2020; Töpf et al. 2020). The highest frequency of this allele in the Genome Aggregation Database is 0.000148 in the Latino/Admixed American population (version 2.1.1). This variant precedes the muscle-specific exon of GFPT1, and patient cDNA studies have shown that it eliminates the first four nucleotides of this exon and results in missense changes of 56 amino acids and a premature stop codon (Selcen et al. 2013). This variant was identified in a homozygous state. Based on the available evidence, the c.686-2A>G variant is classified as pathogenic for GFPT1-related myasthenic syndrome. -
GFPT1-related disorder Pathogenic:1
The GFPT1 c.686-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with congenital myasthenic syndrome (see for example, Selcen et al. 2013. PubMed ID: 23794683; Yiş U et al. 2017. PubMed ID: 28464723; Natera-de Benito et al. 2017. PubMed ID: 29054425). In vitro functional study suggests this variant impacts protein function (Patient 6 in Figure 3, Selcen et al. 2013. PubMed ID: 23794683). This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-69581446-T-C). Variants that disrupt the consensus splice acceptor site in GFPT1 are expected to be pathogenic. This variant is interpreted as pathogenic.. -
Congenital myasthenic syndrome 4C;C3552335:Congenital myasthenic syndrome 12 Pathogenic:1
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not provided Pathogenic:1
GFPT1: PVS1, PM3, PM2:Supporting, PS3:Supporting -
Abnormality of the musculature Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at