chr9-128219106-A-G

Position:

• chr9-128219106-A-G

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.443A>G​(p.Gln148Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q148K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 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 chr9-128219105-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.963
• PP5: Variant 9-128219106-A-G is Pathogenic according to our data. Variant chr9-128219106-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542676.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.443A>G	p.Gln148Arg	missense_variant	4/22	ENST00000372923.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1	ENST00000372923.8	c.443A>G	p.Gln148Arg	missense_variant	4/22	1	NM_004408.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 31 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 20, 2017	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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to be de novo in individuals affected with epilepsy, psychomotor retardation and hypotonia (PMID: 27806796 [Paper in Chinese]). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 148 of the DNM1 protein (p.Gln148Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	The c.443A>G;p.(Gln148Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 542676; PMID: 27806796; 31920647) - PS4_supporting. This variant is not present in population databases (rs1554772959; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clivar ID: 495249- c.442C>A (p.Gln148Lys)) - PM5. Missense variant in DNM1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. 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 likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;T;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;.;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;.;D;.;D;.
Vest4		0.85
MutPred		0.90		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.97
MPC		2.5
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554772959; hg19: chr9-130981385;