rs1057517670

Variant names:

• chr3-147413405-G-C
• rs1057517670
• NM_003412.4:c.1198G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_003412.4(ZIC1):​c.1198G>C​(p.Gly400Arg) variant causes a missense 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G400V) has been classified as Uncertain significance.

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

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]

ZIC1 Gene-Disease associations (from GenCC):

• craniosynostosis 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia
• structural brain anomalies with impaired intellectual development and craniosynostosis

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated oxycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dandy-Walker syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746
• PP5: Variant 3-147413405-G-C is Pathogenic according to our data. Variant chr3-147413405-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372164.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC1	NM_003412.4	c.1198G>C	p.Gly400Arg	missense_variant	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.1198G>C	p.Gly400Arg	missense_variant	Exon 3 of 3	1	NM_003412.4	ENSP00000282928.4
ZIC1	ENST00000488404.5	c.262G>C	p.Gly88Arg	missense_variant	Exon 3 of 3	5		ENSP00000419664.1
ZIC1	ENST00000472523.1	n.521+19463G>C		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:1

Revision: no assertion criteria provided

Submissions by phenotype

Craniosynostosis 6 Pathogenic:1

Jan 15, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.42		Gain of glycosylation at Y401 (P = 0.0012);
MVP		0.30
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.68
gMVP		0.70
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057517670; hg19: chr3-147131192;