rs1554767317

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_004408.4(DNM1):c.134G>A(p.Ser45Asn) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNM1
NM_004408.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.49

Publications

1 publications found

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]

DNM1 links:

CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CIZ1 Gene-Disease associations (from GenCC):

dystonia 23
Inheritance: Unknown Classification: MODERATE Submitted by: Genomics England PanelApp
inherited dystonia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CIZ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_004408.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 9-128203604-G-A is Pathogenic according to our data. Variant chr9-128203604-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520840.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
DNM1	NM_004408.4 link	c.134G>A	p.Ser45Asn	missense_variant	Exon 1 of 22	ENST00000372923.8	NP_004399.2	Q05193-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8 link	c.134G>A	p.Ser45Asn	missense_variant	Exon 1 of 22	1	NM_004408.4	ENSP00000362014.4		Q05193-1
DNM1	ENST00000634267.2 link	c.134G>A	p.Ser45Asn	missense_variant	Exon 1 of 22	5		ENSP00000489096.1		A0A0U1RQP1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1395346

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694148

African (AFR)

AF:

0.00

AC:

AN:

28818

American (AMR)

AF:

0.00

AC:

AN:

36986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24302

East Asian (EAS)

AF:

0.00

AC:

AN:

32050

South Asian (SAS)

AF:

0.00

AC:

AN:

80196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4966

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084188

Other (OTH)

AF:

0.00

AC:

AN:

57350

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A

Pathogenic:1

Feb 04, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with DNM1-related encephalopathy (PMID:¬†28667181). ClinVar contains an entry for this variant (Variation ID: 520840). TThis variant has been reported to affect DNM1 protein function, also known as Dyn1 (PMID: 11553700, 19084268, 29668686). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces serine with asparagine at codon 45 of the DNM1 protein (p.Ser45Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. -

Inborn genetic diseases

Pathogenic:1

Oct 15, 2015

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;.;.;.;.;T;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

H;H;H;H;.;H;.;H;.

PhyloP100

8.5

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.7

D;D;D;D;.;D;.;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D;D;.;D;.;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D

Polyphen

0.99

D;.;D;.;.;B;.;D;.

Vest4

0.85

MutPred

0.96

Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);Loss of ubiquitination at K44 (P = 0.0818);

MVP

0.93

MPC

1.7

ClinPred

1.0

GERP RS

4.1

PromoterAI

0.031

Neutral

(source)

Varity_R

0.99

gMVP

0.99

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over