Genetic Variant ZIC5:p.Pro394_Pro397del (chr13-99970413-TGGCGGCGGCGGC-T) – 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.1179_1190delGCCGCCGCCGCC(p.Pro394_Pro397del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,106,504 control chromosomes in the GnomAD database, including 174 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.0039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0043 ( 174 hom. )

Consequence

ZIC5
NM_033132.5 disruptive_inframe_deletion

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 478 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5 link	c.1179_1190delGCCGCCGCCGCC	p.Pro394_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000267294.5	NP_149123.3	Q96T25
ZIC5	NR_146224.1 link	n.1485_1496delGCCGCCGCCGCC		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.1179_1190delGCCGCCGCCGCC	p.Pro394_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4	Q96T25
ENSG00000297638	ENST00000749511.1 link	n.135+310_135+321delGGCGGCGGCGGC		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1 link	n.104+304_104+315delGGCGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00391

AC:

477

AN:

121978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00503

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00359

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.00495

Gnomad FIN

AF:

0.000789

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00361

Gnomad OTH

AF:

0.00491

GnomAD2 exomes

AF:

0.000608

AC:

AN:

60812

AF XY:

0.000673

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000329

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000556

Gnomad NFE exome

AF:

0.000842

Gnomad OTH exome

AF:

0.00158

GnomAD4 exome

AF:

0.00427

AC:

4202

AN:

984426

Hom.:

174

AF XY:

0.00429

AC XY:

2028

AN XY:

472502

show subpopulations

African (AFR)

AF:

0.00485

AC:

AN:

17928

American (AMR)

AF:

0.00390

AC:

AN:

6416

Ashkenazi Jewish (ASJ)

AF:

0.000870

AC:

AN:

11500

East Asian (EAS)

AF:

0.00333

AC:

AN:

14432

South Asian (SAS)

AF:

0.00274

AC:

AN:

30970

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

12956

Middle Eastern (MID)

AF:

0.00211

AC:

AN:

2838

European-Non Finnish (NFE)

AF:

0.00433

AC:

3694

AN:

852626

Other (OTH)

AF:

0.00598

AC:

208

AN:

34760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

185

370

556

741

926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00392

AC:

478

AN:

122078

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

223

AN XY:

59662

show subpopulations

African (AFR)

AF:

0.00504

AC:

179

AN:

35516

American (AMR)

AF:

0.00359

AC:

AN:

12826

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

2964

East Asian (EAS)

AF:

0.00502

AC:

AN:

3586

South Asian (SAS)

AF:

0.00498

AC:

AN:

3616

European-Finnish (FIN)

AF:

0.000789

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.00362

AC:

198

AN:

54764

Other (OTH)

AF:

0.00486

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

106

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

=188/12

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-TGGCGGCGGCGGCGGCGGCGGC

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