Genetic Variant ZIC5:p.Pro393_Pro397dup (chr13-99970413-T-TGGCGGCGGCGGCGGC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_033132.5(ZIC5):c.1176_1190dupGCCGCCGCCGCCGCC(p.Pro393_Pro397dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZIC5
NM_033132.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.56

Publications

9 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: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_033132.5

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5 link	c.1176_1190dupGCCGCCGCCGCCGCC	p.Pro393_Pro397dup	disruptive_inframe_insertion	Exon 1 of 2	ENST00000267294.5	NP_149123.3	Q96T25
ZIC5	NR_146224.1 link	n.1482_1496dupGCCGCCGCCGCCGCC		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.1176_1190dupGCCGCCGCCGCCGCC	p.Pro393_Pro397dup	disruptive_inframe_insertion	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4	Q96T25
ENSG00000297638	ENST00000749511.1 link	n.135+307_135+321dupGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1 link	n.104+301_104+315dupGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

121980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000313

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000834

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000730

Gnomad OTH

AF:

0.000613

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000427

AC:

AN:

984578

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

472578

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17932

American (AMR)

AF:

0.00

AC:

AN:

6422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11504

East Asian (EAS)

AF:

0.0000692

AC:

AN:

14460

South Asian (SAS)

AF:

0.0000646

AC:

AN:

30972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2840

European-Non Finnish (NFE)

AF:

0.0000446

AC:

AN:

852730

Other (OTH)

AF:

0.0000288

AC:

AN:

34762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000139

AC:

AN:

121980

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

59564

show subpopulations

African (AFR)

AF:

0.000141

AC:

AN:

35420

American (AMR)

AF:

0.000313

AC:

AN:

12798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2964

East Asian (EAS)

AF:

0.000834

AC:

AN:

3596

South Asian (SAS)

AF:

0.00

AC:

AN:

3634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.0000730

AC:

AN:

54774

Other (OTH)

AF:

0.000613

AC:

AN:

1630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

118

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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13-99970413-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over