rs545142847

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong

The ENST00000634267.2(DNM1):​c.2545G>A​(p.Gly849Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000858 in 1,595,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 6/8 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G849E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

DNM1
ENST00000634267.2 missense

Scores

7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.56
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

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: 5.1645 (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.
BP4
Computational evidence support a benign effect (MetaRNN=0.0040893257).
BP6
Variant 9-128254660-G-A is Benign according to our data. Variant chr9-128254660-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476065.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.2541G>A p.Ser847Ser synonymous_variant Exon 22 of 22 ENST00000372923.8 NP_004399.2 Q05193-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNM1ENST00000634267.2 linkc.2545G>A p.Gly849Arg missense_variant Exon 22 of 22 5 ENSP00000489096.1 A0A0U1RQP1
DNM1ENST00000372923.8 linkc.2541G>A p.Ser847Ser synonymous_variant Exon 22 of 22 1 NM_004408.4 ENSP00000362014.4 Q05193-1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
151856
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:
0.00408
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000278
AC:
65
AN:
233556
Hom.:
0
AF XY:
0.000218
AC XY:
28
AN XY:
128280
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00339
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000276
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000796
AC:
115
AN:
1444024
Hom.:
0
Cov.:
32
AF XY:
0.0000723
AC XY:
52
AN XY:
718750
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00227
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.0000998
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
151974
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
AN XY:
74262
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00428
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000854
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.000251
AC:
29
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
Jul 06, 2017
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1
May 04, 2017
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DNM1-related disorder Benign:1
Nov 28, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
11
DANN
Benign
0.92
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.42
T
MetaRNN
Benign
0.0041
T
Sift4G
Benign
0.20
T
Vest4
0.19
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs545142847; hg19: chr9-131016939; COSMIC: COSV57855686; COSMIC: COSV57855686; API