NM_004408.4:c.1409G>C

Variant names:

• chr9-128234094-G-C
• rs763830358
• NM_004408.4:c.1409G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R470H) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 31A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 31B

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4218505).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	NM_004408.4	MANE Select	c.1409G>C	p.Arg470Pro	missense	Exon 11 of 22	NP_004399.2
	DNM1	NM_001374269.1		c.1409G>C	p.Arg470Pro	missense	Exon 11 of 22	NP_001361198.1
	DNM1	NM_001288739.2		c.1409G>C	p.Arg470Pro	missense	Exon 11 of 22	NP_001275668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	ENST00000372923.8	TSL:1 MANE Select	c.1409G>C	p.Arg470Pro	missense	Exon 11 of 22	ENSP00000362014.4
	DNM1	ENST00000486160.3	TSL:1	c.1409G>C	p.Arg470Pro	missense	Exon 11 of 22	ENSP00000420045.1
	DNM1	ENST00000634267.2	TSL:5	c.1409G>C	p.Arg470Pro	missense	Exon 11 of 22	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

African (AFR) AF: 0.00 AC: 0 AN: 31970

American (AMR) AF: 0.00 AC: 0 AN: 37438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24770

East Asian (EAS) AF: 0.00 AC: 0 AN: 36434

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084960

Other (OTH) AF: 0.00 AC: 0 AN: 58332

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 v4.9

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
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.34	N
PhyloP100		3.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.37
Sift	Benign	0.96	T
Sift4G	Benign	0.69	T
Polyphen		0.71	P
Vest4		0.78
MutPred		0.49		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
Mutation Taster		=71/29	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs763830358; hg19: chr9-130996373;