rs1057517669

Positions:

• chr3-147413411-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_003412.4(ZIC1):​c.1204G>T​(p.Glu402Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZIC1 NM_003412.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.11

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 7 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. Fraction of 0.104 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-147413411-G-T is Pathogenic according to our data. Variant chr3-147413411-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 372163.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-147413411-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIC1	NM_003412.4	c.1204G>T	p.Glu402Ter	stop_gained	3/3	ENST00000282928.5	NP_003403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIC1	ENST00000282928.5	c.1204G>T	p.Glu402Ter	stop_gained	3/3	1	NM_003412.4	ENSP00000282928	P1
ZIC1	ENST00000488404.5	c.271G>T	p.Glu91Ter	stop_gained	3/3	5		ENSP00000419664
ZIC1	ENST00000472523.1	n.521+19469G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
Vest4		0.69
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1057517669; hg19: chr3-147131198;