chr10-93316788-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_013451.4(MYOF):c.5624C>T(p.Thr1875Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,624 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
MYOF
NM_013451.4 missense
NM_013451.4 missense
Scores
10
5
2
Clinical Significance
Conservation
PhyloP100: 9.96
Genes affected
MYOF (HGNC:3656): (myoferlin) Mutations in dysferlin, a protein associated with the plasma membrane, can cause muscle weakness that affects both proximal and distal muscles. The protein encoded by this gene is a type II membrane protein that is structurally similar to dysferlin. It is a member of the ferlin family and associates with both plasma and nuclear membranes. The protein contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. Two transcript variants encoding different isoforms have been found for this gene. Other possible variants have been detected, but their full-length nature has not been determined. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874
BS2
High AC in GnomAdExome4 at 41 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYOF | NM_013451.4 | c.5624C>T | p.Thr1875Met | missense_variant | 50/54 | ENST00000359263.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYOF | ENST00000359263.9 | c.5624C>T | p.Thr1875Met | missense_variant | 50/54 | 1 | NM_013451.4 | P1 | |
MYOF | ENST00000358334.9 | c.5585C>T | p.Thr1862Met | missense_variant | 49/53 | 1 | |||
MYOF | ENST00000463743.5 | c.*183C>T | 3_prime_UTR_variant, NMD_transcript_variant | 30/34 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151900Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.0000521 AC: 13AN: 249504Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135368
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461606Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 727126
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152018Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74288
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2022 | The c.5624C>T (p.T1875M) alteration is located in exon 50 (coding exon 50) of the MYOF gene. This alteration results from a C to T substitution at nucleotide position 5624, causing the threonine (T) at amino acid position 1875 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.59
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at