9-128234094-G-C

Variant names:

• chr9-128234094-G-C
• NM_004408.4:c.1409G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004408.4(DNM1):​c.1409G>C​(p.Arg470Pro) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4218505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.1409G>C	p.Arg470Pro	missense_variant	Exon 11 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.1409G>C	p.Arg470Pro	missense_variant	Exon 11 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.1409G>C	p.Arg470Pro	missense_variant	Exon 11 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407800 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	29
DANN	Benign	0.79
DEOGEN2	Uncertain	0.69	D;.;.;.;.;.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;.;.;D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.34	N;N;N;N;.;N;.;N;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;D;D;.;D;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.96	T;T;T;T;.;T;.;.;.
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T
Polyphen		0.71	P;.;P;.;.;P;.;P;.
Vest4		0.78
MutPred		0.49		Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);.;Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);
MVP		0.86
MPC		1.7
ClinPred		0.50	T
GERP RS		2.8
Varity_R		0.91
gMVP		0.92

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130996373;