rs1554774587

Variant names:

• chr9-128222543-G-A
• rs1554774587
• NM_004408.4:c.1075G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004408.4(DNM1):​c.1075G>A​(p.Gly359Arg) 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. 13/20 in silico tools predict a damaging 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, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DNM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: 5.1795 (above the threshold of 3.09). Trascript score misZ: 5.021 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.986
• PP5: Variant 9-128222543-G-A is Pathogenic according to our data. Variant chr9-128222543-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520737.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	c.1075G>A	p.Gly359Arg	missense_variant	Exon 8 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.1075G>A	p.Gly359Arg	missense_variant	Exon 8 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.1075G>A	p.Gly359Arg	missense_variant	Exon 8 of 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, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Pathogenic:1

May 14, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 359 of the DNM1 protein (p.Gly359Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has been observed to be de novo in individuals affected with early infantile epileptic encephalopathy (PMID: 28667181, Invitae). ClinVar contains an entry for this variant (Variation ID: 520737). For these reasons, this variant has been classified as 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. A variant that disrupts the p.Gly359 amino acid residue in DNM1 has been observed in an affected individual (PMID: 25262651). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. -

Inborn genetic diseases Pathogenic:1

Oct 12, 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	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;H;.;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.5	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		1.0	D;.;D;.;.;D;.;D;.
Vest4		0.95
MutPred		0.93		Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);Gain of methylation at G359 (P = 0.0218);
MVP		0.93
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554774587; hg19: chr9-130984822;