rs752575279
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PVS1_ModeratePP3BP6_Very_Strong
The NM_004408.4(DNM1):c.2536C>T(p.Arg846Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000814 in 1,596,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000076 ( 0 hom. )
Consequence
DNM1
NM_004408.4 stop_gained, splice_region
NM_004408.4 stop_gained, splice_region
Scores
4
4
2
Splicing: ADA: 0.9658
2
Clinical Significance
Conservation
PhyloP100: 2.91
Genes affected
DNM1 (HGNC:2972): (dynamin 1) This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0227 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
Variant 9-128254655-C-T is Benign according to our data. Variant chr9-128254655-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 488945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNM1 | NM_004408.4 | c.2536C>T | p.Arg846Ter | stop_gained, splice_region_variant | 22/22 | ENST00000372923.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM1 | ENST00000372923.8 | c.2536C>T | p.Arg846Ter | stop_gained, splice_region_variant | 22/22 | 1 | NM_004408.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000343 AC: 8AN: 233572Hom.: 0 AF XY: 0.0000468 AC XY: 6AN XY: 128286
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GnomAD4 exome AF: 0.00000762 AC: 11AN: 1444074Hom.: 0 Cov.: 32 AF XY: 0.00000835 AC XY: 6AN XY: 718776
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74280
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 31 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Uncertain
T
MutationTaster
Benign
D;D;D;D
Sift4G
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
Find out detailed SpliceAI scores and Pangolin per-transcript scores at