chr9-128166354-C-A

Variant names:

• chr9-128166354-C-A
• rs11549260
• NM_001131016.2:c.2540G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001257975.2(CIZ1):​c.2708G>T​(p.Arg903Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,409,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R903Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CIZ1 NM_001257975.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.883
• Publications: 0 publications found

Genes affected

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15238598).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257975.2. 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
	CIZ1	NM_001131016.2	MANE Select	c.2540G>T	p.Arg847Leu	missense	Exon 17 of 17	NP_001124488.1
	CIZ1	NM_001257975.2		c.2708G>T	p.Arg903Leu	missense	Exon 18 of 18	NP_001244904.1
	CIZ1	NM_012127.3		c.2540G>T	p.Arg847Leu	missense	Exon 17 of 17	NP_036259.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIZ1	ENST00000372938.10	TSL:1 MANE Select	c.2540G>T	p.Arg847Leu	missense	Exon 17 of 17	ENSP00000362029.5
	CIZ1	ENST00000415526.5	TSL:1	c.2306G>T	p.Arg769Leu	missense	Exon 15 of 15	ENSP00000398011.1
	CIZ1	ENST00000372954.5	TSL:1	c.2300G>T	p.Arg767Leu	missense	Exon 17 of 17	ENSP00000362045.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409314 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 696008

African (AFR) AF: 0.00 AC: 0 AN: 32300

American (AMR) AF: 0.00 AC: 0 AN: 36728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36800

South Asian (SAS) AF: 0.00 AC: 0 AN: 79876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084466

Other (OTH) AF: 0.00 AC: 0 AN: 58370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.88
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.062
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		0.82	P
Vest4		0.31
MutPred		0.23		Loss of MoRF binding (P = 0.04)
MVP		0.24
MPC		0.78
ClinPred		0.63	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.090
gMVP		0.63
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11549260; hg19: chr9-130928633;