Genetic Variant ZIC5:p.Pro392_Pro397dup (chr13-99970413-T-TGGCGGCGGCGGCGGCGGC) – 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.1173_1190dupGCCGCCGCCGCCGCCGCC(p.Pro392_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 0.000049 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000017 ( 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 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5 link	c.1173_1190dupGCCGCCGCCGCCGCCGCC	p.Pro392_Pro397dup	disruptive_inframe_insertion	Exon 1 of 2	ENST00000267294.5	NP_149123.3	Q96T25
ZIC5	NR_146224.1 link	n.1479_1496dupGCCGCCGCCGCCGCCGCC		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.1173_1190dupGCCGCCGCCGCCGCCGCC	p.Pro392_Pro397dup	disruptive_inframe_insertion	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4	Q96T25
ENSG00000297638	ENST00000749511.1 link	n.135+304_135+321dupGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1 link	n.104+298_104+315dupGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000492

AC:

AN:

121980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000156

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:

0.0000730

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000173

AC:

AN:

984584

Hom.:

Cov.:

AF XY:

0.0000212

AC XY:

AN XY:

472584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

0.00

AC:

AN:

14460

South Asian (SAS)

AF:

0.0000323

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:

0.0000188

AC:

AN:

852734

Other (OTH)

AF:

0.00

AC:

AN:

34764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.390

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000491

AC:

AN:

122080

Hom.:

Cov.:

AF XY:

0.0000335

AC XY:

AN XY:

59662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

35516

American (AMR)

AF:

0.000156

AC:

AN:

12826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2964

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00

AC:

AN:

3616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.0000730

AC:

AN:

54766

Other (OTH)

AF:

0.00

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

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