NM_001278464.2:c.344C>T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS1_Supporting
The NM_001278464.2(DNM1L):c.344C>T(p.Thr115Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,597,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001278464.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNM1L | NM_001278464.2 | c.344C>T | p.Thr115Met | missense_variant | Exon 5 of 21 | ENST00000553257.6 | NP_001265393.1 | |
DNM1L | NM_012062.5 | c.305C>T | p.Thr102Met | missense_variant | Exon 4 of 20 | ENST00000549701.6 | NP_036192.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNM1L | ENST00000553257.6 | c.344C>T | p.Thr115Met | missense_variant | Exon 5 of 21 | 2 | NM_001278464.2 | ENSP00000449089.1 | ||
DNM1L | ENST00000549701.6 | c.305C>T | p.Thr102Met | missense_variant | Exon 4 of 20 | 1 | NM_012062.5 | ENSP00000450399.1 |
Frequencies
GnomAD3 genomes AF: 0.000257 AC: 39AN: 151888Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000282 AC: 70AN: 247996Hom.: 0 AF XY: 0.000320 AC XY: 43AN XY: 134472
GnomAD4 exome AF: 0.000238 AC: 344AN: 1445702Hom.: 0 Cov.: 27 AF XY: 0.000271 AC XY: 195AN XY: 720110
GnomAD4 genome AF: 0.000257 AC: 39AN: 152006Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74274
ClinVar
Submissions by phenotype
not provided Uncertain:4
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 102 of the DNM1L protein (p.Thr102Met). This variant is present in population databases (rs201929226, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive encephalopathy (PMID: 29110115). This variant is also known as p.Thr115Met. ClinVar contains an entry for this variant (Variation ID: 214308). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Reported as de novo in one individual with autism or intellectual disability; detailed clinical information was not reported (PMID: 34356170); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 35741050, 34356170, 29110115, 30850373) -
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not specified Uncertain:1
Variant summary: DNM1L c.305C>T (p.Thr102Met) results in a non-conservative amino acid change located in the Dynamin, GTPase domain (IPR001401) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 247996 control chromosomes (gnomAD). c.305C>T has been reported in the literature in an individual affected with developmental delay and neurological impairment (example: Hogarth_2018). This report does not provide unequivocal conclusions about association of the variant with Encephalopathy, Lethal, Due To Defective Mitochondrial Peroxisomal Fission 1, Autosomal Recessive. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Hogarth_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29110115, 34356170). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inborn genetic diseases Uncertain:1
The c.305C>T (p.T102M) alteration is located in exon 4 (coding exon 4) of the DNM1L gene. This alteration results from a C to T substitution at nucleotide position 305, causing the threonine (T) at amino acid position 102 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Optic atrophy 5;C3280660:Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at