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rs1554767313

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_004408.4(DNM1):c.127G>A(p.Gly43Ser) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43D) has been classified 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

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.49
Variant links:
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, 3 uncertain in NM_004408.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-128203598-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 968753.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant where missense usually causes diseases, DNM1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 9-128203597-G-A is Pathogenic according to our data. Variant chr9-128203597-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNM1NM_004408.4 linkuse as main transcriptc.127G>A p.Gly43Ser missense_variant 1/22 ENST00000372923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM1ENST00000372923.8 linkuse as main transcriptc.127G>A p.Gly43Ser missense_variant 1/221 NM_004408.4 A1Q05193-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1398472
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
695748
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31 Pathogenic:4
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 14, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyMar 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant p.G43S in DNM1 (NM_004408.4) has been previously reported as a de novo mutation in a patient with Lennox Gestaut syndrome.Protein modelling had revealed a damaging effect (Nakashima M et al,2016). The variant has been submitted to ClinVar as Pathogenic. The p.G43S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G43S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.127 in DNM1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingDASAJun 10, 2022The c.127G>A;p.(Gly43Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 520545; PMID: 26611353) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 26611353) - PS2. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Dynamin_N) - PM1. This variant is not present in population databases:rs1554767313, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 30, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
Cadd
Pathogenic
33
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;.;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.7
H;H;H;H;.;H;.;H;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.4
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D;D;D;D;.;D;.;.;.
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;.;.;D;.;D;.
Vest4
0.88
MutPred
0.93
Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);
MVP
0.96
MPC
2.3
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.99
gMVP
0.95

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554767313; hg19: chr9-130965876; API