chr9-128219192-G-C

Position:

• chr9-128219192-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_004408.4(DNM1):​c.529G>C​(p.Ala177Pro) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 10 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, 0.981
• PP5: Variant 9-128219192-G-C is Pathogenic according to our data. Variant chr9-128219192-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 156557.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1	NM_004408.4	c.529G>C	p.Ala177Pro	missense_variant	4/22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.529G>C	p.Ala177Pro	missense_variant	4/22	1	NM_004408.4	ENSP00000362014	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;H;H;.;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.;D;.
Vest4		0.97
MutPred		0.92		Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);Gain of catalytic residue at P176 (P = 0.0188);
MVP		0.98
MPC		2.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
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: rs587777860; hg19: chr9-130981471;