rs869312702

Variant names:

• chr9-128203609-G-A
• rs869312702
• NM_004408.4:c.139G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-128203609-G-A
• chr9-128203609-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004408.4(DNM1):​c.139G>A​(p.Val47Met) variant causes a missense change. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V47V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.74
• Publications: 4 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]

CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CIZ1 Gene-Disease associations (from GenCC):

• dystonia 23

  Inheritance: Unknown Classification: MODERATE Submitted by: Genomics England PanelApp
• inherited dystonia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_004408.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 9-128203609-G-A is Pathogenic according to our data. Variant chr9-128203609-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224142.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.139G>A	p.Val47Met	missense	Exon 1 of 22	NP_004399.2	Q05193-1
	DNM1	NM_001374269.1		c.139G>A	p.Val47Met	missense	Exon 1 of 22	NP_001361198.1	A0A994J7J4
	DNM1	NM_001288739.2		c.139G>A	p.Val47Met	missense	Exon 1 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.139G>A	p.Val47Met	missense	Exon 1 of 22	ENSP00000362014.4	Q05193-1
	DNM1	ENST00000486160.3	TSL:1	c.139G>A	p.Val47Met	missense	Exon 1 of 22	ENSP00000420045.1	Q05193-2
	DNM1	ENST00000634267.2	TSL:5	c.139G>A	p.Val47Met	missense	Exon 1 of 22	ENSP00000489096.1	A0A0U1RQP1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1391336 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 692260

African (AFR) AF: 0.00 AC: 0 AN: 28748

American (AMR) AF: 0.00 AC: 0 AN: 36214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24238

East Asian (EAS) AF: 0.00 AC: 0 AN: 31848

South Asian (SAS) AF: 0.00 AC: 0 AN: 79822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4910

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082326

Other (OTH) AF: 0.00 AC: 0 AN: 57094

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Developmental and epileptic encephalopathy, 31A (2)
1	-	-	Cerebellar ataxia;C0026827:Hypotonia;C0036572:Seizure;C0038273:Stereotypic movement disorder;C0543888:Epileptic encephalopathy;C0557874:Global developmental delay (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		6.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.91		Gain of disorder (P = 0.1132)
MVP		0.95
MPC		2.4
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.0011	Neutral
Varity_R		0.92
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869312702; hg19: chr9-130965888;