NM_004408.4:c.1493+14delC

Variant names:

• chr9-128239524-TC-T
• rs371426966
• NM_004408.4:c.1493+14delC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_004408.4(DNM1):​c.1493+14delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,609,628 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00062 (4 hom.)
• Consequence: DNM1 NM_004408.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.57
• 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: AR, AD Classification: DEFINITIVE, MODERATE 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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.

• BP6: Variant 9-128239524-TC-T is Benign according to our data. Variant chr9-128239524-TC-T is described in ClinVar as Benign. ClinVar VariationId is 476061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	NM_004408.4	MANE Select	c.1493+14delC		intron	N/A	NP_004399.2	Q05193-1
	DNM1	NM_001374269.1		c.1493+14delC		intron	N/A	NP_001361198.1	A0A994J7J4
	DNM1	NM_001288739.2		c.1493+14delC		intron	N/A	NP_001275668.1	Q05193-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	ENST00000372923.8	TSL:1 MANE Select	c.1493+14delC		intron	N/A	ENSP00000362014.4	Q05193-1
	DNM1	ENST00000486160.3	TSL:1	c.1493+14delC		intron	N/A	ENSP00000420045.1	Q05193-2
	DNM1	ENST00000634267.2	TSL:5	c.1493+14delC		intron	N/A	ENSP00000489096.1	A0A0U1RQP1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 62 AN: 149584 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

Gnomad ASJ AF: 0.00233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00443

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000429

Gnomad OTH AF: 0.000973

GnomAD2 exomes AF: 0.00102 AC: 255 AN: 251058 AF XY: 0.00112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.000616 AC: 899 AN: 1459934 Hom.: 4 Cov.: 32 AF XY: 0.000716 AC XY: 520 AN XY: 726232

African (AFR) AF: 0.0000299 AC: 1 AN: 33420

American (AMR) AF: 0.000246 AC: 11 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.00485 AC: 418 AN: 86178

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5760

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1110520

Other (OTH) AF: 0.00106 AC: 64 AN: 60300

GnomAD4 genome AF: 0.000414 AC: 62 AN: 149694 Hom.: 0 Cov.: 31 AF XY: 0.000439 AC XY: 32 AN XY: 72974

African (AFR) AF: 0.0000247 AC: 1 AN: 40472

American (AMR) AF: 0.0000671 AC: 1 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 8 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00443 AC: 21 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000429 AC: 29 AN: 67578

Other (OTH) AF: 0.000962 AC: 2 AN: 2078

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.000359

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 31A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs371426966; hg19: chr9-131001803;