9-128214278-C-T

Variant names:

• chr9-128214278-C-T
• rs2502731
• NM_004408.4:c.162-3953C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004408.4(DNM1):​c.162-3953C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 151,916 control chromosomes in the GnomAD database, including 30,450 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (30450 hom., cov: 31)
• Consequence: DNM1 NM_004408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 27 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.162-3953C>T		intron_variant	Intron 1 of 21	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.162-3953C>T		intron_variant	Intron 1 of 21	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.162-3953C>T		intron_variant	Intron 1 of 21	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95941 AN: 151798 Hom.: 30427 Cov.: 31

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.633

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.632 AC: 96007 AN: 151916 Hom.: 30450 Cov.: 31 AF XY: 0.631 AC XY: 46824 AN XY: 74258

African (AFR) AF: 0.585 AC: 24241 AN: 41404

American (AMR) AF: 0.714 AC: 10896 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2091 AN: 3470

East Asian (EAS) AF: 0.661 AC: 3412 AN: 5160

South Asian (SAS) AF: 0.689 AC: 3324 AN: 4822

European-Finnish (FIN) AF: 0.574 AC: 6044 AN: 10528

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43801 AN: 67946

Other (OTH) AF: 0.635 AC: 1342 AN: 2114

Alfa AF: 0.643 Hom.: 132576

Bravo AF: 0.641

Asia WGS AF: 0.699 AC: 2429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.98
DANN	Benign	0.35
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2502731; hg19: chr9-130976557;