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rs769485700

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_004408.4(DNM1):c.1399C>T(p.Arg467Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,569,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R467R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DNM1
NM_004408.4 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.04
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 Uncertain_significance. Variant got 1 ACMG points.

PP2
Missense variant where missense usually causes diseases, DNM1

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNM1NM_004408.4 linkuse as main transcriptc.1399C>T p.Arg467Cys missense_variant 11/22 ENST00000372923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM1ENST00000372923.8 linkuse as main transcriptc.1399C>T p.Arg467Cys missense_variant 11/221 NM_004408.4 A1Q05193-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000120
AC:
17
AN:
1417112
Hom.:
0
Cov.:
30
AF XY:
0.0000114
AC XY:
8
AN XY:
701102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000135
Gnomad4 SAS exome
AF:
0.0000748
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000459
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152296
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000255
AC:
3

ClinVar

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

Submissions by phenotype

Developmental and epileptic encephalopathy, 31 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 31, 2022ClinVar contains an entry for this variant (Variation ID: 521971). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DNM1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 467 of the DNM1 protein (p.Arg467Cys). -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.77
D;.;.;.;.;.;T;.;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.99
D;.;.;D;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.70
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.062
T
MutationAssessor
Benign
1.7
L;L;L;L;.;L;.;L;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.6
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
0.67
Sift
Benign
0.039
D;T;T;T;.;D;.;.;.
Sift4G
Benign
0.067
T;T;T;T;T;T;T;T;T
Polyphen
1.0
D;.;D;.;.;D;.;D;.
Vest4
0.88
MutPred
0.62
Loss of disorder (P = 0.0144);Loss of disorder (P = 0.0144);Loss of disorder (P = 0.0144);Loss of disorder (P = 0.0144);Loss of disorder (P = 0.0144);Loss of disorder (P = 0.0144);.;Loss of disorder (P = 0.0144);Loss of disorder (P = 0.0144);
MVP
0.89
MPC
1.8
ClinPred
0.71
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.61
gMVP
0.92

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: rs769485700; hg19: chr9-130996363; API