Genetic Variant ZIC5:p.Pro395_Pro397del (chr13-99970413-TGGCGGCGGC-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3BS1BS2

The NM_033132.5(ZIC5):c.1182_1190delGCCGCCGCC(p.Pro395_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 0.00908 in 1,106,596 control chromosomes in the GnomAD database, including 307 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 0)

Exomes 𝑓: 0.0089 ( 298 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: Benign. The variant received -9 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_033132.5

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0102 (1248/122066) while in subpopulation EAS AF = 0.0441 (158/3584). AF 95% confidence interval is 0.0385. There are 9 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 1248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5 link	c.1182_1190delGCCGCCGCC	p.Pro395_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000267294.5	NP_149123.3	Q96T25
ZIC5	NR_146224.1 link	n.1488_1496delGCCGCCGCC		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.1182_1190delGCCGCCGCC	p.Pro395_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4	Q96T25
ENSG00000297638	ENST00000749511.1 link	n.135+313_135+321delGGCGGCGGC		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1 link	n.104+307_104+315delGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1249

AN:

121966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00536

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.0442

Gnomad SAS

AF:

0.00660

Gnomad FIN

AF:

0.00205

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00986

Gnomad OTH

AF:

0.0160

GnomAD2 exomes

AF:

0.00109

AC:

AN:

60812

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00164

Gnomad ASJ exome

AF:

0.00211

Gnomad EAS exome

AF:

0.000515

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00894

AC:

8797

AN:

984530

Hom.:

298

AF XY:

0.00912

AC XY:

4309

AN XY:

472552

show subpopulations

African (AFR)

AF:

0.00424

AC:

AN:

17932

American (AMR)

AF:

0.0125

AC:

AN:

6420

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

238

AN:

11502

East Asian (EAS)

AF:

0.0350

AC:

506

AN:

14458

South Asian (SAS)

AF:

0.00346

AC:

107

AN:

30966

European-Finnish (FIN)

AF:

0.00100

AC:

AN:

12956

Middle Eastern (MID)

AF:

0.00739

AC:

AN:

2840

European-Non Finnish (NFE)

AF:

0.00867

AC:

7395

AN:

852702

Other (OTH)

AF:

0.0104

AC:

361

AN:

34754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.551

Heterozygous variant carriers

428

856

1284

1712

2140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0102

AC:

1248

AN:

122066

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

621

AN XY:

59656

show subpopulations

African (AFR)

AF:

0.00535

AC:

190

AN:

35516

American (AMR)

AF:

0.0167

AC:

214

AN:

12826

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

2962

East Asian (EAS)

AF:

0.0441

AC:

158

AN:

3584

South Asian (SAS)

AF:

0.00636

AC:

AN:

3616

European-Finnish (FIN)

AF:

0.00205

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.00986

AC:

540

AN:

54756

Other (OTH)

AF:

0.0164

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

114

172

229

286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00210

Hom.:

118

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=180/20

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-TGGCGGCGGCGGCGGCGGCGGCGGC

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