13-99970413-TGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr13-99970413-TGGCGGCGGC-T
• rs71114653
• NM_033132.5:c.1182_1190delGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 9 publications found

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]

ENSG00000297638 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033132.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC5	NM_033132.5	MANE Select	c.1182_1190delGCCGCCGCC	p.Pro395_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	NP_149123.3	Q96T25
	ZIC5	NR_146224.1		n.1488_1496delGCCGCCGCC		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC5	ENST00000267294.5	TSL:1 MANE Select	c.1182_1190delGCCGCCGCC	p.Pro395_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000267294.4	Q96T25
	ENSG00000297638	ENST00000749511.1		n.135+313_135+321delGGCGGCGGC		intron	N/A
	ENSG00000297638	ENST00000749512.1		n.104+307_104+315delGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1249 AN: 121966 Hom.: 9 Cov.: 0

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: 66 AN: 60812 AF XY: 0.00121

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

African (AFR) AF: 0.00424 AC: 76 AN: 17932

American (AMR) AF: 0.0125 AC: 80 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: 13 AN: 12956

Middle Eastern (MID) AF: 0.00739 AC: 21 AN: 2840

European-Non Finnish (NFE) AF: 0.00867 AC: 7395 AN: 852702

Other (OTH) AF: 0.0104 AC: 361 AN: 34754

GnomAD4 genome AF: 0.0102 AC: 1248 AN: 122066 Hom.: 9 Cov.: 0 AF XY: 0.0104 AC XY: 621 AN XY: 59656

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: 83 AN: 2962

East Asian (EAS) AF: 0.0441 AC: 158 AN: 3584

South Asian (SAS) AF: 0.00636 AC: 23 AN: 3616

European-Finnish (FIN) AF: 0.00205 AC: 13 AN: 6340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 138

European-Non Finnish (NFE) AF: 0.00986 AC: 540 AN: 54756

Other (OTH) AF: 0.0164 AC: 27 AN: 1646

Alfa AF: 0.00210 Hom.: 118

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=180/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs71114653; hg19: chr13-100622667; COSMIC: COSV57436663;