chr9-128203604-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_004408.4(DNM1):c.134G>A(p.Ser45Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
DNM1
NM_004408.4 missense
NM_004408.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 8.49
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]
CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_004408.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DNM1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
?
Variant 9-128203604-G-A is Pathogenic according to our data. Variant chr9-128203604-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520840.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.134G>A | p.Ser45Asn | missense_variant | 1/22 | ENST00000372923.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM1 | ENST00000372923.8 | c.134G>A | p.Ser45Asn | missense_variant | 1/22 | 1 | NM_004408.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1395346Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 694148
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
1395346
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
694148
Gnomad4 AFR exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 15, 2015 | - - |
Developmental and epileptic encephalopathy, 31 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2019 | This sequence change replaces serine with asparagine at codon 45 of the DNM1 protein (p.Ser45Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. TThis variant has been reported to affect DNM1 protein function, also known as Dyn1 (PMID: 11553700, 19084268, 29668686). This variant has been observed to be de novo in an individual affected with DNM1-related encephalopathy (PMID: 28667181). ClinVar contains an entry for this variant (Variation ID: 520840). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;.;H;.;H;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;.;D;.;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
D;.;D;.;.;B;.;D;.
Vest4
MutPred
Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at