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rs1554774587

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_004408.4(DNM1):c.1075G>A(p.Gly359Arg) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G359A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

DNM1
NM_004408.4 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004408.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-128222544-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156559.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, 0.986
PP5
Variant 9-128222543-G-A is Pathogenic according to our data. Variant chr9-128222543-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520737.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.1075G>A p.Gly359Arg missense_variant 8/22 ENST00000372923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM1ENST00000372923.8 linkuse as main transcriptc.1075G>A p.Gly359Arg missense_variant 8/221 NM_004408.4 A1Q05193-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMay 14, 2018This sequence change replaces glycine with arginine at codon 359 of the DNM1 protein (p.Gly359Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with early infantile epileptic encephalopathy (PMID: 28667181, Invitae). ClinVar contains an entry for this variant (Variation ID: 520737). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. A variant that disrupts the p.Gly359 amino acid residue in DNM1 has been observed in an affected individual (PMID: 25262651). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.88
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;.;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Pathogenic
3.7
H;H;H;H;.;H;.;H;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-7.5
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
1.0
D;.;D;.;.;D;.;D;.
Vest4
0.95
MutPred
0.93
Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);
MVP
0.93
MPC
2.6
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
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: rs1554774587; hg19: chr9-130984822; API