9-128237193-G-C

Variant names:

• chr9-128237193-G-C
• rs7022174
• NM_004408.4:c.1423-2252G>C

Variant summary

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

The NM_004408.4(DNM1):​c.1423-2252G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,936 control chromosomes in the GnomAD database, including 14,411 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 0.38 (14411 hom., cov: 32)
• Consequence: DNM1 NM_004408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884
• Publications: 6 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

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.1423-2252G>C		intron	N/A	NP_004399.2
	DNM1	NM_001374269.1		c.1423-2252G>C		intron	N/A	NP_001361198.1
	DNM1	NM_001288739.2		c.1423-2252G>C		intron	N/A	NP_001275668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	ENST00000372923.8	TSL:1 MANE Select	c.1423-2252G>C		intron	N/A	ENSP00000362014.4
	DNM1	ENST00000486160.3	TSL:1	c.1423-2252G>C		intron	N/A	ENSP00000420045.1
	DNM1	ENST00000634267.2	TSL:5	c.1423-2252G>C		intron	N/A	ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57034 AN: 151818 Hom.: 14355 Cov.: 32

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.376 AC: 57152 AN: 151936 Hom.: 14411 Cov.: 32 AF XY: 0.377 AC XY: 28010 AN XY: 74278

African (AFR) AF: 0.717 AC: 29658 AN: 41380

American (AMR) AF: 0.273 AC: 4162 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3466

East Asian (EAS) AF: 0.494 AC: 2551 AN: 5160

South Asian (SAS) AF: 0.402 AC: 1939 AN: 4826

European-Finnish (FIN) AF: 0.233 AC: 2459 AN: 10542

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14409 AN: 67978

Other (OTH) AF: 0.358 AC: 755 AN: 2106

Alfa AF: 0.127 Hom.: 211

Bravo AF: 0.392

Asia WGS AF: 0.460 AC: 1597 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.72
DANN	Benign	0.43
PhyloP100		-0.88
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: rs7022174; hg19: chr9-130999472;