9-128242289-A-G

Position:

• chr9-128242289-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The ENST00000372923.8(DNM1):​c.1615A>G​(p.Lys539Glu) 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K539K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM1 ENST00000372923.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.27

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]

ACMG classification

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 0 benign, 2 uncertain in ENST00000372923.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM1. . Gene score misZ 5.1795 (greater than the threshold 3.09). Trascript score misZ 5.021 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 31, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy 31B, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• PP5: Variant 9-128242289-A-G is Pathogenic according to our data. Variant chr9-128242289-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542678.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1	NM_004408.4	c.1615A>G	p.Lys539Glu	missense_variant	15/22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.1615A>G	p.Lys539Glu	missense_variant	15/22	1	NM_004408.4	ENSP00000362014	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual affected with seizures and developmental delay (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 539 of the DNM1 protein (p.Lys539Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.8	M;M;M;M;.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.76
Sift	Benign	0.042	D;D;D;D;.;D;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T
Polyphen		0.89	P;.;P;.;.;.;.;P;.
Vest4		0.65
MutPred		0.65		Loss of ubiquitination at K539 (P = 0.0134);Loss of ubiquitination at K539 (P = 0.0134);Loss of ubiquitination at K539 (P = 0.0134);Loss of ubiquitination at K539 (P = 0.0134);.;Loss of ubiquitination at K539 (P = 0.0134);.;Loss of ubiquitination at K539 (P = 0.0134);Loss of ubiquitination at K539 (P = 0.0134);
MVP		0.85
MPC		2.1
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.83

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554781553; hg19: chr9-131004568;