9-128208739-A-G

Variant names:

• chr9-128208739-A-G
• rs7875406
• NM_004408.4:c.161+5108A>G

Variant summary

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

The NM_004408.4(DNM1):​c.161+5108A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,004 control chromosomes in the GnomAD database, including 1,649 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 0.11 (1649 hom., cov: 31)
• Consequence: DNM1 NM_004408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 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.161+5108A>G		intron	N/A	NP_004399.2
	DNM1	NM_001374269.1		c.161+5108A>G		intron	N/A	NP_001361198.1
	DNM1	NM_001288739.2		c.161+5108A>G		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.161+5108A>G		intron	N/A	ENSP00000362014.4
	DNM1	ENST00000486160.3	TSL:1	c.161+5108A>G		intron	N/A	ENSP00000420045.1
	DNM1	ENST00000634267.2	TSL:5	c.161+5108A>G		intron	N/A	ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17362 AN: 151886 Hom.: 1646 Cov.: 31

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0999

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

GnomAD4 genome AF: 0.114 AC: 17377 AN: 152004 Hom.: 1649 Cov.: 31 AF XY: 0.116 AC XY: 8637 AN XY: 74282

African (AFR) AF: 0.233 AC: 9650 AN: 41408

American (AMR) AF: 0.0723 AC: 1106 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.355 AC: 1835 AN: 5168

South Asian (SAS) AF: 0.109 AC: 526 AN: 4808

European-Finnish (FIN) AF: 0.0800 AC: 845 AN: 10562

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0452 AC: 3072 AN: 67980

Other (OTH) AF: 0.0993 AC: 210 AN: 2114

Alfa AF: 0.0710 Hom.: 382

Bravo AF: 0.120

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.74
PhyloP100		-0.48
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: rs7875406; hg19: chr9-130971018;