rs1554767317

Variant names:

• chr9-128203604-G-A
• rs1554767317
• NM_004408.4:c.134G>A

Variant summary

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

The NM_001374269.1(DNM1):​c.134G>A​(p.Ser45Asn) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNM1 NM_001374269.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.49
• 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]

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001374269.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 9-128203604-G-A is Pathogenic according to our data. Variant chr9-128203604-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374269.1. 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.134G>A	p.Ser45Asn	missense	Exon 1 of 22	NP_004399.2
	DNM1	NM_001374269.1		c.134G>A	p.Ser45Asn	missense	Exon 1 of 22	NP_001361198.1
	DNM1	NM_001288739.2		c.134G>A	p.Ser45Asn	missense	Exon 1 of 22	NP_001275668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	ENST00000372923.8	TSL:1 MANE Select	c.134G>A	p.Ser45Asn	missense	Exon 1 of 22	ENSP00000362014.4
	DNM1	ENST00000486160.3	TSL:1	c.134G>A	p.Ser45Asn	missense	Exon 1 of 22	ENSP00000420045.1
	DNM1	ENST00000634267.2	TSL:5	c.134G>A	p.Ser45Asn	missense	Exon 1 of 22	ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1395346 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 694148

African (AFR) AF: 0.00 AC: 0 AN: 28818

American (AMR) AF: 0.00 AC: 0 AN: 36986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24302

East Asian (EAS) AF: 0.00 AC: 0 AN: 32050

South Asian (SAS) AF: 0.00 AC: 0 AN: 80196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4966

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084188

Other (OTH) AF: 0.00 AC: 0 AN: 57350

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 31A (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		8.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.96		Loss of ubiquitination at K44 (P = 0.0818)
MVP		0.93
MPC		1.7
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		0.031	Neutral
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554767317; hg19: chr9-130965883;