rs371329389

Variant names:

• chr9-128187868-G-A
• rs371329389
• NM_001131016.2:c.353C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001131016.2(CIZ1):​c.353C>T​(p.Thr118Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000685 in 730,282 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: CIZ1 NM_001131016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13152698).
• BS2: High AC in GnomAd4 at 10 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001131016.2. 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.353C>T	p.Thr118Ile	missense	Exon 4 of 17	NP_001124488.1	Q9ULV3-1
	CIZ1	NM_001257975.2		c.443C>T	p.Thr148Ile	missense	Exon 4 of 18	NP_001244904.1	F5H2X7
	CIZ1	NM_012127.3		c.353C>T	p.Thr118Ile	missense	Exon 4 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.353C>T	p.Thr118Ile	missense	Exon 4 of 17	ENSP00000362029.5	Q9ULV3-1
	CIZ1	ENST00000415526.5	TSL:1	c.140-2092C>T		intron	N/A	ENSP00000398011.1	H0Y5D5
	CIZ1	ENST00000372954.5	TSL:1	c.287-2092C>T		intron	N/A	ENSP00000362045.1	Q9ULV3-3

Frequencies

GnomAD3 genomes AF: 0.0000668 AC: 10 AN: 149734 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000376 AC: 9 AN: 239656 AF XY: 0.0000230

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: 0.0000838

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000689 AC: 40 AN: 580548 Hom.: 0 Cov.: 0 AF XY: 0.0000567 AC XY: 18 AN XY: 317362

African (AFR) AF: 0.00 AC: 0 AN: 17002

American (AMR) AF: 0.00 AC: 0 AN: 41766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19804

East Asian (EAS) AF: 0.00 AC: 0 AN: 35190

South Asian (SAS) AF: 0.00 AC: 0 AN: 60212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2658

European-Non Finnish (NFE) AF: 0.000114 AC: 37 AN: 323156

Other (OTH) AF: 0.0000985 AC: 3 AN: 30464

GnomAD4 genome AF: 0.0000668 AC: 10 AN: 149734 Hom.: 0 Cov.: 30 AF XY: 0.0000822 AC XY: 6 AN XY: 72998

African (AFR) AF: 0.00 AC: 0 AN: 41002

American (AMR) AF: 0.00 AC: 0 AN: 14994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67568

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.0085
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Uncertain	0.018	D
Polyphen		0.48	P
Vest4		0.57
MVP		0.75
MPC		0.52
ClinPred		0.16	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.21
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs371329389; hg19: chr9-130950147;