rs1554767317

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

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

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 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, 0.98
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 rank MANE Protein UniProt
DNM1NM_004408.4 linkc.134G>A p.Ser45Asn 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.134G>A p.Ser45Asn missense_variant Exon 1 of 22 1 NM_004408.4 ENSP00000362014.4 Q05193-1
DNM1ENST00000634267.2 linkc.134G>A p.Ser45Asn 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;AS_VQSR
AF:
0.00
AC:
0
AN:
1395346
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
694148
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Pathogenic:1
Feb 04, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). 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). TThis variant has been reported to affect DNM1 protein function, also known as Dyn1 (PMID: 11553700, 19084268, 29668686). 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. 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. -

Inborn genetic diseases Pathogenic:1
Oct 15, 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
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
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
1.0
D
MutationAssessor
Pathogenic
4.6
H;H;H;H;.;H;.;H;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-2.7
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;D;D;.;D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D
Polyphen
0.99
D;.;D;.;.;B;.;D;.
Vest4
0.85
MutPred
0.96
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
0.93
MPC
1.7
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.99
gMVP
0.99

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: rs1554767317; hg19: chr9-130965883; API