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GeneBe

rs1554773487

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_004408.4(DNM1):c.713G>T(p.Ser238Ile) 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: 9.97
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 9 ACMG points.

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, 0.969
PP5
Variant 9-128220205-G-T is Pathogenic according to our data. Variant chr9-128220205-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 520714.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNM1NM_004408.4 linkuse as main transcriptc.713G>T p.Ser238Ile missense_variant 6/22 ENST00000372923.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNM1ENST00000372923.8 linkuse as main transcriptc.713G>T p.Ser238Ile missense_variant 6/221 NM_004408.4 A1Q05193-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
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 GeneticsJul 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
32
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.;.;.;T;.;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;.;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H;H;H;.;H;.;H;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.3
D;D;D;D;.;D;.;.;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D;D;.;D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D;D
Polyphen
0.97
D;.;D;.;.;D;.;D;.
Vest4
0.97
MutPred
0.81
Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);Loss of disorder (P = 0.0265);
MVP
0.97
MPC
2.6
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.94

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: rs1554773487; hg19: chr9-130982484; API