rs1382648008

Variant names:

• chr9-128203504-C-A
• rs1382648008
• NM_004408.4:c.34C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004408.4(DNM1):​c.34C>A​(p.Leu12Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,383,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.34C>A	p.Leu12Met	missense	Exon 1 of 22	NP_004399.2	Q05193-1
	DNM1	NM_001374269.1		c.34C>A	p.Leu12Met	missense	Exon 1 of 22	NP_001361198.1	A0A994J7J4
	DNM1	NM_001288739.2		c.34C>A	p.Leu12Met	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.34C>A	p.Leu12Met	missense	Exon 1 of 22	ENSP00000362014.4	Q05193-1
	DNM1	ENST00000486160.3	TSL:1	c.34C>A	p.Leu12Met	missense	Exon 1 of 22	ENSP00000420045.1	Q05193-2
	DNM1	ENST00000634267.2	TSL:5	c.34C>A	p.Leu12Met	missense	Exon 1 of 22	ENSP00000489096.1	A0A0U1RQP1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 165000 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383944 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 686924

African (AFR) AF: 0.00 AC: 0 AN: 28550

American (AMR) AF: 0.00 AC: 0 AN: 34664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23904

East Asian (EAS) AF: 0.00 AC: 0 AN: 31226

South Asian (SAS) AF: 0.00 AC: 0 AN: 78066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48462

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076746

Other (OTH) AF: 0.00 AC: 0 AN: 56778

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.60
Sift	Benign	0.046	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.45		Gain of disorder (P = 0.0791)
MVP		0.72
MPC		1.4
ClinPred		0.77	D
GERP RS		3.1
PromoterAI		0.038	Neutral
Varity_R		0.17
gMVP		0.61
Mutation Taster		=55/45	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1382648008; hg19: chr9-130965783;