chr9-128231118-A-G

Variant names:

• chr9-128231118-A-G
• rs16930313
• NM_004408.4:c.1336-2903A>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.1336-2903A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 149,578 control chromosomes in the GnomAD database, including 4,054 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 0.21 (4054 hom., cov: 31)
• Consequence: DNM1 NM_004408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.1336-2903A>G		intron_variant	Intron 10 of 21	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.1336-2903A>G		intron_variant	Intron 10 of 21	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.1336-2903A>G		intron_variant	Intron 10 of 21	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 30797 AN: 149476 Hom.: 4043 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.206 AC: 30835 AN: 149578 Hom.: 4054 Cov.: 31 AF XY: 0.208 AC XY: 15154 AN XY: 72852

African (AFR) AF: 0.365 AC: 14910 AN: 40824

American (AMR) AF: 0.138 AC: 2065 AN: 14922

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 476 AN: 3438

East Asian (EAS) AF: 0.342 AC: 1707 AN: 4984

South Asian (SAS) AF: 0.277 AC: 1308 AN: 4726

European-Finnish (FIN) AF: 0.136 AC: 1356 AN: 9978

Middle Eastern (MID) AF: 0.176 AC: 50 AN: 284

European-Non Finnish (NFE) AF: 0.125 AC: 8449 AN: 67434

Other (OTH) AF: 0.195 AC: 406 AN: 2084

Alfa AF: 0.163 Hom.: 4141

Bravo AF: 0.209

Asia WGS AF: 0.284 AC: 985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	8.3
DANN	Benign	0.70
PhyloP100		-0.15
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: rs16930313; hg19: chr9-130993397;