rs752575279

Variant names:

• chr9-128254655-C-T
• rs752575279
• ENST00000634267.2:c.2540C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PVS1_Moderate PP3 BP6

The NM_004408.4(DNM1):​c.2536C>T​(p.Arg846*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000814 in 1,596,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: DNM1 NM_004408.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9658
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.91
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0227 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-128254655-C-T is Benign according to our data. Variant chr9-128254655-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488945.

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.2536C>T	p.Arg846*	stop_gained splice_region	Exon 22 of 22	NP_004399.2	Q05193-1
	DNM1	NM_001288739.2		c.2536C>T	p.Arg846*	stop_gained splice_region	Exon 22 of 22	NP_001275668.1	Q05193-2
	DNM1	NM_001005336.3		c.*17C>T		splice_region	Exon 23 of 23	NP_001005336.1	Q05193-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	ENST00000634267.2	TSL:5	c.2540C>T	p.Pro847Leu	missense	Exon 22 of 22	ENSP00000489096.1	A0A0U1RQP1
	DNM1	ENST00000372923.8	TSL:1 MANE Select	c.2536C>T	p.Arg846*	stop_gained splice_region	Exon 22 of 22	ENSP00000362014.4	Q05193-1
	DNM1	ENST00000486160.3	TSL:1	c.2536C>T	p.Arg846*	stop_gained splice_region	Exon 22 of 22	ENSP00000420045.1	Q05193-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000343 AC: 8 AN: 233572 AF XY: 0.0000468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1444074 Hom.: 0 Cov.: 32 AF XY: 0.00000835 AC XY: 6 AN XY: 718776

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.000112 AC: 5 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111714

Other (OTH) AF: 0.00 AC: 0 AN: 60106

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41380

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000173 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.34	T
MetaRNN	Uncertain	0.47	T
PhyloP100		2.9
Sift4G	Uncertain	0.015	D
Vest4		0.39
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=18/182	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.94

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

Other links and lift over

dbSNP: rs752575279; hg19: chr9-131016934; COSMIC: COSV57848527; COSMIC: COSV57848527;