NM_004408.4:c.312G>A

Variant names:

• chr9-128218658-G-A
• rs2229917
• NM_004408.4:c.312G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004408.4(DNM1):​c.312G>A​(p.Glu104Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.072 in 1,613,176 control chromosomes in the GnomAD database, including 5,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1342 hom., cov: 31)
  • Exomes 𝑓: 0.068 (4147 hom.)
• Consequence: DNM1 NM_004408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.62
• Publications: 9 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 9-128218658-G-A is Benign according to our data. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128218658-G-A is described in CliVar as Benign. Clinvar id is 380778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.312G>A	p.Glu104Glu	synonymous_variant	Exon 3 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.312G>A	p.Glu104Glu	synonymous_variant	Exon 3 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.312G>A	p.Glu104Glu	synonymous_variant	Exon 3 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16569 AN: 151940 Hom.: 1335 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0745

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0702

Gnomad FIN AF: 0.0394

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.0717 AC: 17944 AN: 250324 AF XY: 0.0713

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.00327

Gnomad FIN exome AF: 0.0385

Gnomad NFE exome AF: 0.0706

Gnomad OTH exome AF: 0.0771

GnomAD4 exome AF: 0.0681 AC: 99515 AN: 1461118 Hom.: 4147 Cov.: 33 AF XY: 0.0686 AC XY: 49865 AN XY: 726746

African (AFR) AF: 0.230 AC: 7707 AN: 33458

American (AMR) AF: 0.0484 AC: 2160 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3050 AN: 26122

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39690

South Asian (SAS) AF: 0.0700 AC: 6034 AN: 86198

European-Finnish (FIN) AF: 0.0406 AC: 2162 AN: 53304

Middle Eastern (MID) AF: 0.135 AC: 778 AN: 5766

European-Non Finnish (NFE) AF: 0.0655 AC: 72825 AN: 1111544

Other (OTH) AF: 0.0783 AC: 4724 AN: 60364

GnomAD4 genome AF: 0.109 AC: 16605 AN: 152058 Hom.: 1342 Cov.: 31 AF XY: 0.105 AC XY: 7827 AN XY: 74326

African (AFR) AF: 0.224 AC: 9257 AN: 41398

American (AMR) AF: 0.0743 AC: 1137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5172

South Asian (SAS) AF: 0.0701 AC: 338 AN: 4824

European-Finnish (FIN) AF: 0.0394 AC: 418 AN: 10602

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0693 AC: 4712 AN: 67978

Other (OTH) AF: 0.107 AC: 227 AN: 2112

Alfa AF: 0.0808 Hom.: 536

Bravo AF: 0.115

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0768

EpiControl AF: 0.0768

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Developmental and epileptic encephalopathy, 31A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Dec 31, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		2.6
Mutation Taster		=94/6	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2229917; hg19: chr9-130980937;