Genetic Variant ZIC5:p.Pro395_Pro397dup (chr13-99970413-T-TGGCGGCGGC) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

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

The ENST00000267294.5(ZIC5):c.1182_1190dupGCCGCCGCC(p.Pro395_Pro397dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00098 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZIC5
ENST00000267294.5 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 ENST00000267294.5

BS2

High AC in GnomAd4 at 180 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000267294.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC5	NM_033132.5	MANE Select	c.1182_1190dupGCCGCCGCC	p.Pro395_Pro397dup	disruptive_inframe_insertion	Exon 1 of 2	NP_149123.3
	ZIC5	NR_146224.1		n.1488_1496dupGCCGCCGCC		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZIC5	ENST00000267294.5	TSL:1 MANE Select	c.1182_1190dupGCCGCCGCC	p.Pro395_Pro397dup	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000267294.4
ENSG00000297638	ENST00000749511.1		n.135+313_135+321dupGGCGGCGGC		intron	N/A
ENSG00000297638	ENST00000749512.1		n.104+307_104+315dupGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

180

AN:

121980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000847

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00273

Gnomad ASJ

AF:

0.00742

Gnomad EAS

AF:

0.00139

Gnomad SAS

AF:

0.00110

Gnomad FIN

AF:

0.000158

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.00123

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000983

AC:

968

AN:

984536

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

431

AN XY:

472562

show subpopulations

African (AFR)

AF:

0.000669

AC:

AN:

17932

American (AMR)

AF:

0.000311

AC:

AN:

6422

Ashkenazi Jewish (ASJ)

AF:

0.00296

AC:

AN:

11502

East Asian (EAS)

AF:

0.000346

AC:

AN:

14460

South Asian (SAS)

AF:

0.000936

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:

0.000975

AC:

831

AN:

852690

Other (OTH)

AF:

0.00158

AC:

AN:

34762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<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:

0.00147

AC:

180

AN:

122080

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

59662

show subpopulations

African (AFR)

AF:

0.000845

AC:

AN:

35516

American (AMR)

AF:

0.00273

AC:

AN:

12826

Ashkenazi Jewish (ASJ)

AF:

0.00742

AC:

AN:

2964

East Asian (EAS)

AF:

0.00139

AC:

AN:

3586

South Asian (SAS)

AF:

0.00111

AC:

AN:

3616

European-Finnish (FIN)

AF:

0.000158

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.00148

AC:

AN:

54766

Other (OTH)

AF:

0.00122

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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 v4.9

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-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over