rs1057517668

Variant names:

• chr3-147413372-C-T
• rs1057517668
• NM_003412.4:c.1165C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003412.4(ZIC1):​c.1165C>T​(p.Gln389*) variant causes a stop gained 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZIC1 NM_003412.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.47

Genes affected

ZIC1 (HGNC:12872): (Zic family member 1) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development. Aberrant expression of this gene is seen in medulloblastoma, a childhood brain tumor. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 4, a related family member on chromosome 3. This gene encodes a transcription factor that can bind and transactivate the apolipoprotein E gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-147413372-C-T is Pathogenic according to our data. Variant chr3-147413372-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372162.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-147413372-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC1	NM_003412.4	c.1165C>T	p.Gln389*	stop_gained	Exon 3 of 3	ENST00000282928.5	NP_003403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC1	ENST00000282928.5	c.1165C>T	p.Gln389*	stop_gained	Exon 3 of 3	1	NM_003412.4	ENSP00000282928.4
ZIC1	ENST00000488404.5	c.229C>T	p.Gln77*	stop_gained	Exon 3 of 3	5		ENSP00000419664.1
ZIC1	ENST00000472523.1	n.521+19430C>T		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Structural brain anomalies with impaired intellectual development and craniosynostosis Pathogenic:1

Jan 14, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 27, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q389X variant in the ZIC1 gene has been reported previously in an individual with craniosynostosis, intellectual disability, and additional cerebral anomalies (Twigg et al., 2015). Functional studies in Xenopus embryos suggest that Q389X is damaging to embryonic development (Twigg et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation as the last 59 amino acids of the ZIC1 protein are lost. The Q389X variant is not observed in large population cohorts (Lek et al., 2016). Additionally, the Q389X variant has occurred de novo in this individual whose reported clinical presentation is consistent with a ZIC1-related disorder. We interpret Q389X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.43
GERP RS		3.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517668; hg19: chr3-147131159; COSMIC: COSV99291777;