Genetic Variant ZIC5:p.Pro398Ser (chr13-99970412-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033132.5(ZIC5):c.1192C>T(p.Pro398Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P398Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZIC5
NM_033132.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.740

Publications

0 publications found

Variant links:

Genes affected

ZIC5 (HGNC:20322): (Zic family member 5) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. The encoded protein may act as a transcriptional repressor. Studies in mouse and Xenopus support a role for this gene in neural crest development. Elevated expression of this gene has been observed in various human cancers and may contribute to cancer progression. This gene is closely linked to a related family member on chromosome 13. [provided by RefSeq, Mar 2017]

ZIC5 links:

ENSG00000297638 (HGNC:):

ENSG00000297638 links:

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ACMG classification

Classification was made for transcript

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=0.103744864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5 link	c.1192C>T	p.Pro398Ser	missense_variant	Exon 1 of 2	ENST00000267294.5	NP_149123.3	Q96T25
ZIC5	NR_146224.1 link	n.1498C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZIC5	ENST00000267294.5 link	c.1192C>T	p.Pro398Ser	missense_variant	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4	Q96T25
ENSG00000297638	ENST00000749511.1 link	n.135+284G>A		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1 link	n.104+278G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1061624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

512196

African (AFR)

AF:

0.00

AC:

AN:

21102

American (AMR)

AF:

0.00

AC:

AN:

9216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14148

East Asian (EAS)

AF:

0.00

AC:

AN:

20778

South Asian (SAS)

AF:

0.00

AC:

AN:

32416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

900360

Other (OTH)

AF:

0.00

AC:

AN:

39430

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1264C>T (p.P422S) alteration is located in exon 1 (coding exon 1) of the ZIC5 gene. This alteration results from a C to T substitution at nucleotide position 1264, causing the proline (P) at amino acid position 422 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.14

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.88

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.52

M_CAP

Benign

0.0084

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.3

PhyloP100

0.74

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.60

REVEL

Benign

0.022

Sift

Benign

0.23

Sift4G

Benign

0.51

Polyphen

0.015

Vest4

0.31

MutPred

0.40

Gain of catalytic residue at P423 (P = 0);

MVP

0.040

ClinPred

0.085

GERP RS

1.4

Varity_R

0.046

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over