rs3003609

Variant names:

• chr9-128222476-C-T
• rs3003609
• NM_004408.4:c.1008C>T

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.1008C>T​(p.Phe336Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,613,764 control chromosomes in the GnomAD database, including 236,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (17223 hom., cov: 32)
  • Exomes 𝑓: 0.54 (219465 hom.)
• Consequence: DNM1 NM_004408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.579
• Publications: 40 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=-0.3).
• BP6: Variant 9-128222476-C-T is Benign according to our data. Variant chr9-128222476-C-T is described in ClinVar as Benign. ClinVar VariationId is 380777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.579 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.1008C>T	p.Phe336Phe	synonymous_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.1008C>T	p.Phe336Phe	synonymous_variant	Exon 8 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.1008C>T	p.Phe336Phe	synonymous_variant	Exon 8 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65773 AN: 151902 Hom.: 17215 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.542 AC: 136150 AN: 251218 AF XY: 0.546

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.599

Gnomad FIN exome AF: 0.534

Gnomad NFE exome AF: 0.543

Gnomad OTH exome AF: 0.542

GnomAD4 exome AF: 0.542 AC: 792635 AN: 1461744 Hom.: 219465 Cov.: 62 AF XY: 0.543 AC XY: 394906 AN XY: 727172

African (AFR) AF: 0.104 AC: 3472 AN: 33476

American (AMR) AF: 0.692 AC: 30922 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 11466 AN: 26130

East Asian (EAS) AF: 0.581 AC: 23062 AN: 39698

South Asian (SAS) AF: 0.581 AC: 50154 AN: 86254

European-Finnish (FIN) AF: 0.541 AC: 28894 AN: 53392

Middle Eastern (MID) AF: 0.478 AC: 2759 AN: 5768

European-Non Finnish (NFE) AF: 0.549 AC: 610119 AN: 1111924

Other (OTH) AF: 0.526 AC: 31787 AN: 60390

GnomAD4 genome AF: 0.433 AC: 65779 AN: 152020 Hom.: 17223 Cov.: 32 AF XY: 0.439 AC XY: 32590 AN XY: 74278

African (AFR) AF: 0.122 AC: 5055 AN: 41506

American (AMR) AF: 0.602 AC: 9193 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1553 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3031 AN: 5152

South Asian (SAS) AF: 0.589 AC: 2833 AN: 4810

European-Finnish (FIN) AF: 0.531 AC: 5611 AN: 10572

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36782 AN: 67928

Other (OTH) AF: 0.465 AC: 982 AN: 2110

Alfa AF: 0.510 Hom.: 98459

Bravo AF: 0.424

Asia WGS AF: 0.570 AC: 1978 AN: 3478

EpiCase AF: 0.540

EpiControl AF: 0.543

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 06, 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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 82. Only high quality variants are reported. -

Developmental and epileptic encephalopathy, 31A Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.0
DANN	Benign	0.87
PhyloP100		0.58
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3003609; hg19: chr9-130984755; COSMIC: COSV57849632; COSMIC: COSV57849632;