rs587777861

Positions:

• chr9-128220016-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_004408.4(DNM1):​c.618G>C​(p.Lys206Asn) variant causes a missense change involving the alteration of a non-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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.09

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Dynamin-type G (size 266) in uniprot entity DYN1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004408.4
• 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, 0.974
• PP5: Variant 9-128220016-G-C is Pathogenic according to our data. Variant chr9-128220016-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 156558.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.618G>C	p.Lys206Asn	missense_variant	5/22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.618G>C	p.Lys206Asn	missense_variant	5/22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.618G>C	p.Lys206Asn	missense_variant	5/22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 02, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2023

Published functional studies demonstrate inhibition of transferrin uptake, abnormal protein aggregation and distribution, and decrease of basal protein levels (PMID: 27066543); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29397573, 25262651, 37900685, 29186148, 30174244, 26611353, 28667181, 23934111, 27066543) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.;T;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;.;H;.;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;.;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.;D;.
Vest4		0.94
MutPred		0.86		Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);Loss of ubiquitination at K206 (P = 0.0161);
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777861; hg19: chr9-130982295;