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rs1554781552

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_004408.4(DNM1):c.1610G>A(p.Gly537Asp) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

DNM1
NM_004408.4 missense

Scores

13
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.94
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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, 0.912
PP5
Variant 9-128242284-G-A is Pathogenic according to our data. Variant chr9-128242284-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521642.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNM1NM_004408.4 linkuse as main transcriptc.1610G>A p.Gly537Asp missense_variant 15/22 ENST00000372923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM1ENST00000372923.8 linkuse as main transcriptc.1610G>A p.Gly537Asp missense_variant 15/221 NM_004408.4 A1Q05193-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.090
Cadd
Pathogenic
32
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;.;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Pathogenic
3.0
M;M;M;M;.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.9
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0010
D;D;D;D;.;D;.;.;.
Sift4G
Uncertain
0.058
T;T;T;T;D;T;T;T;T
Polyphen
1.0
D;.;D;.;.;.;.;D;.
Vest4
0.82
MutPred
0.76
Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);.;Gain of relative solvent accessibility (P = 0.0023);.;Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP
0.78
MPC
2.6
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.90

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: rs1554781552; hg19: chr9-131004563; API