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rs1554774708

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_004408.4(DNM1):c.1190G>A(p.Gly397Asp) 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DNM1
NM_004408.4 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

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 11 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004408.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, DNM1
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 9-128222854-G-A is Pathogenic according to our data. Variant chr9-128222854-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520569.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-128222854-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNM1NM_004408.4 linkuse as main transcriptc.1190G>A p.Gly397Asp missense_variant 9/22 ENST00000372923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM1ENST00000372923.8 linkuse as main transcriptc.1190G>A p.Gly397Asp missense_variant 9/221 NM_004408.4 A1Q05193-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 17, 2014The c.1190G>A (p.G397D) alteration is located in exon 9 (coding exon 9) of the DNM1 gene. This alteration results from a G to A substitution at nucleotide position 1190, causing the glycine (G) at amino acid position 397 to be replaced by an aspartic acid (D). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the DNM1 c.1190G>A alteration was not observed among 5,837 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project, and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP)._x000D_ Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered nucleotide is conserved throughout evolution:_x000D_ The c.1190G nucleotide is completely conserved in available vertebrate species._x000D_ _x000D_ The altered amino acid is conserved throughout evolution:_x000D_ The p.G397 amino acid is completely conserved in available vertebrate species. The c.1190G>A (p.G397D) alteration is located in coding exon 9 of the DNM1 gene. This alteration results from a G to A substitution at nucleotide position 1190, resulting in an amino acid substitution of aspartic acid (D) for glycine (G) at codon 397. The alteration is predicted deleterious by in silico models:_x000D_ The p.G397D alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses._x000D_ _x000D_ The alteration is predicted not to affect splicing by in silico models:_x000D_ Based on BDGP and ESEfinder splice site in silico tools, this alteration does not have any significant effect on the native acceptor/donor splice site; however, direct evidence is unavailable. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
Cadd
Pathogenic
32
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;.;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.57
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.7
H;H;H;H;.;H;.;H;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-6.5
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0020
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
0.91
MutPred
0.81
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP
0.97
MPC
2.0
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
1.0

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: rs1554774708; hg19: chr9-130985133; API