rs1554767313

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_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. The variant was absent in control chromosomes in GnomAD project. 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 (★★).

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a domain Dynamin-type G (size 266) in uniprot entity DYN1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004408.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the DNM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: 5.1795 (above the threshold of 3.09). Trascript score misZ: 5.021 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 31, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy 31B, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
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 rank MANE Protein UniProt
DNM1NM_004408.4 linkc.127G>A p.Gly43Ser missense_variant Exon 1 of 22 ENST00000372923.8 NP_004399.2 Q05193-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNM1ENST00000372923.8 linkc.127G>A p.Gly43Ser missense_variant Exon 1 of 22 1 NM_004408.4 ENSP00000362014.4 Q05193-1
DNM1ENST00000634267.2 linkc.127G>A p.Gly43Ser missense_variant Exon 1 of 22 5 ENSP00000489096.1 A0A0U1RQP1

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, 31A Pathogenic:4
Jun 10, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The 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 -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 14, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Mar 15, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1
Nov 30, 2015
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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;.
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