rs141704244
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001130987.2(DYSF):c.4911G>A(p.Lys1637=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001130987.2 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.4911G>A | p.Lys1637= | splice_region_variant, synonymous_variant | 44/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.4794G>A | p.Lys1598= | splice_region_variant, synonymous_variant | 43/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.4911G>A | p.Lys1637= | splice_region_variant, synonymous_variant | 44/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.4794G>A | p.Lys1598= | splice_region_variant, synonymous_variant | 43/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251434Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135890
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727234
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The synonymous variant p.K1637= in DYSF (NM_001130987.2) has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. This p.Lys1637 type of mutation causes no change in the protein that is produced, which is why it's considered as synonymous mutation. This variant also falls at the last nucleotide of exon 43 of the DYSF coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (Buratti et al, 2007, Zhang et al, 1998). The nucleotide c.4911 in DYSF is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. In the absence of another reportable variant molecular diagnosis is not confirmed. - |
Qualitative or quantitative defects of dysferlin Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 27, 2022 | This sequence change affects codon 1598 of the DYSF mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DYSF protein. This variant also falls at the last nucleotide of exon 43, which is part of the consensus splice site for this exon. This variant is present in population databases (rs141704244, gnomAD 0.05%). This variant has been observed in individual(s) with limb-girdle muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 288089). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.4794G nucleotide in the DYSF gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 27195159). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 01, 2024 | This sequence change is a synonymous (silent) variant altering the last base of exon 44 of DYSF that is predicted to impact splicing (SpliceAI). The highest population minor allele frequency in the population database gnomAD v4.0 is 0.04% (39/91,076 alleles) in the South Asian population, which is consistent with recessive disease. This variant has been observed with a second variant of uncertain significance in an individual with limb-girdle muscular dystrophy (LGMD, PMID: 30564623). Another variant at the same nucleotide position (c.4911G>T) with a similar predicted splice impact to the variant under assessment has been classified as likely pathogenic for LGMD (ClinVar ID: ID: 94331; PMID: 21520333, 27195159, 30564623, 33610434, 36983702). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3, PS1_Moderate. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 12, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at