rs1554767313

chr9-128203597-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004408.4(DNM1):c.127G>A(p.Gly43Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43D) has been classified 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.49

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004408.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-128203598-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 968753.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, DNM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 9-128203597-G-A is Pathogenic according to our data. Variant chr9-128203597-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1	NM_004408.4	c.127G>A	p.Gly43Ser	missense_variant	1/22	ENST00000372923.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1	ENST00000372923.8	c.127G>A	p.Gly43Ser	missense_variant	1/22	1	NM_004408.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398472 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 695748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 31 Pathogenic:4

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.G43S in DNM1 (NM_004408.4) has been previously reported as a de novo mutation in a patient with Lennox Gestaut syndrome.Protein modelling had revealed a damaging effect (Nakashima M et al,2016). The variant has been submitted to ClinVar as Pathogenic. The p.G43S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G43S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.127 in DNM1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.127G>A;p.(Gly43Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 520545; PMID: 26611353) - PS4. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 26611353) - PS2. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Dynamin_N) - PM1. This variant is not present in population databases:rs1554767313, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 15, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.7	H;H;H;H;.;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.;D;.
Vest4		0.88
MutPred		0.93		Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);Loss of stability (P = 0.0601);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.99
gMVP		0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554767313; hg19: chr9-130965876;