rs1554772959

Variant names:

• chr9-128219106-A-G
• rs1554772959
• NM_004408.4:c.443A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004408.4(DNM1):​c.443A>G​(p.Gln148Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q148K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32
• Publications: 3 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004408.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-128219105-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 495249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 9-128219106-A-G is Pathogenic according to our data. Variant chr9-128219106-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 542676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.443A>G	p.Gln148Arg	missense	Exon 4 of 22	NP_004399.2	Q05193-1
	DNM1	NM_001374269.1		c.443A>G	p.Gln148Arg	missense	Exon 4 of 22	NP_001361198.1	A0A994J7J4
	DNM1	NM_001288739.2		c.443A>G	p.Gln148Arg	missense	Exon 4 of 22	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.443A>G	p.Gln148Arg	missense	Exon 4 of 22	ENSP00000362014.4	Q05193-1
	DNM1	ENST00000486160.3	TSL:1	c.443A>G	p.Gln148Arg	missense	Exon 4 of 22	ENSP00000420045.1	Q05193-2
	DNM1	ENST00000634267.2	TSL:5	c.443A>G	p.Gln148Arg	missense	Exon 4 of 22	ENSP00000489096.1	A0A0U1RQP1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Developmental and epileptic encephalopathy, 31A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.90		Loss of sheet (P = 0.0817)
MVP		0.97
MPC		2.5
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554772959; hg19: chr9-130981385;