13-99970413-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

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

The NM_033132.5(ZIC5):​c.1179_1190dupGCCGCCGCCGCC​(p.Pro394_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 0.00024 ( 0 hom., cov: 0)
Exomes 𝑓: 0.00016 ( 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]

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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 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZIC5NM_033132.5 linkc.1179_1190dupGCCGCCGCCGCC p.Pro394_Pro397dup disruptive_inframe_insertion Exon 1 of 2 ENST00000267294.5 NP_149123.3 Q96T25
ZIC5NR_146224.1 linkn.1485_1496dupGCCGCCGCCGCC non_coding_transcript_exon_variant Exon 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZIC5ENST00000267294.5 linkc.1179_1190dupGCCGCCGCCGCC p.Pro394_Pro397dup disruptive_inframe_insertion Exon 1 of 2 1 NM_033132.5 ENSP00000267294.4 Q96T25
ENSG00000297638ENST00000749511.1 linkn.135+310_135+321dupGGCGGCGGCGGC intron_variant Intron 1 of 1
ENSG00000297638ENST00000749512.1 linkn.104+304_104+315dupGGCGGCGGCGGC intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
AF:
0.000238
AC:
29
AN:
121980
Hom.:
0
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.000113
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000781
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000834
Gnomad SAS
AF:
0.000275
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000365
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000155
AC:
153
AN:
984558
Hom.:
0
Cov.:
5
AF XY:
0.000171
AC XY:
81
AN XY:
472570
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:
0
AN:
17932
American (AMR)
AF:
0.00
AC:
0
AN:
6422
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
11504
East Asian (EAS)
AF:
0.000277
AC:
4
AN:
14460
South Asian (SAS)
AF:
0.000129
AC:
4
AN:
30970
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
12956
Middle Eastern (MID)
AF:
0.000352
AC:
1
AN:
2840
European-Non Finnish (NFE)
AF:
0.000163
AC:
139
AN:
852712
Other (OTH)
AF:
0.000144
AC:
5
AN:
34762
⚠️ 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: 0.376
Heterozygous variant carriers
0
8
17
25
34
42
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000238
AC:
29
AN:
122080
Hom.:
0
Cov.:
0
AF XY:
0.000251
AC XY:
15
AN XY:
59662
show subpopulations
African (AFR)
AF:
0.000113
AC:
4
AN:
35516
American (AMR)
AF:
0.0000780
AC:
1
AN:
12826
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2964
East Asian (EAS)
AF:
0.000837
AC:
3
AN:
3586
South Asian (SAS)
AF:
0.000277
AC:
1
AN:
3616
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6340
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
138
European-Non Finnish (NFE)
AF:
0.000365
AC:
20
AN:
54766
Other (OTH)
AF:
0.00
AC:
0
AN:
1646
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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

Splicing

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

Publications

Other links and lift over

dbSNP: rs71114653; hg19: chr13-100622667; API