Variant chr13-99970388-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033132.5(ZIC5):c.1216C>T(p.Pro406Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,370,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

ZIC5
NM_033132.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.349

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040779382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIC5	NM_033132.5 link	c.1216C>T	p.Pro406Ser	missense_variant	1/2	ENST00000267294.5	NP_149123.3	Q96T25
ZIC5	NR_146224.1 link	n.1522C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIC5	ENST00000267294.5 link	c.1216C>T	p.Pro406Ser	missense_variant	1/2	1	NM_033132.5	ENSP00000267294.4		Q96T25

Frequencies

GnomAD3 genomes

AF:

0.0000214

AC:

AN:

140426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000696

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:

0.00

Gnomad OTH

AF:

0.000526

GnomAD4 exome

AF:

0.00000163

AC:

AN:

1230156

Hom.:

Cov.:

AF XY:

0.00000166

AC XY:

AN XY:

601032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000203

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000214

AC:

AN:

140426

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68622

show subpopulations

Gnomad4 AFR

AF:

0.0000269

Gnomad4 AMR

AF:

0.0000696

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000526

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.1288C>T (p.P430S) 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 1288, causing the proline (P) at amino acid position 430 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

0.27

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.58

M_CAP

Benign

0.046

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.67

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.2

REVEL

Benign

0.020

Sift

Benign

0.80

Sift4G

Benign

1.0

Polyphen

0.42

Vest4

0.067

MutPred

0.28

Gain of catalytic residue at K433 (P = 0);

MVP

0.24

ClinPred

0.10

GERP RS

2.0

Varity_R

0.069

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over