chr13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T

Variant names:

• chr13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T
• rs71114653
• NM_033132.5:c.1170_1190delGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_033132.5(ZIC5):​c.1170_1190delGCCGCCGCCGCCGCCGCCGCC​(p.Pro391_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 0.00867 in 1,106,640 control chromosomes in the GnomAD database, including 1,781 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0091 (1778 hom.)
• Consequence: ZIC5 NM_033132.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_033132.5
• BP6: Variant 13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chr13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 713917.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00909 (8952/984562) while in subpopulation SAS AF = 0.0476 (1473/30970). AF 95% confidence interval is 0.0455. There are 1778 homozygotes in GnomAdExome4. There are 4912 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAd4 at 640 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5	c.1170_1190delGCCGCCGCCGCCGCCGCCGCC	p.Pro391_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000267294.5	NP_149123.3
ZIC5	NR_146224.1	n.1476_1496delGCCGCCGCCGCCGCCGCCGCC		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC5	ENST00000267294.5	c.1170_1190delGCCGCCGCCGCCGCCGCCGCC	p.Pro391_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4
ENSG00000297638	ENST00000749511.1	n.135+301_135+321delGGCGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1	n.104+295_104+315delGGCGGCGGCGGCGGCGGCGGC		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 640 AN: 121978 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00594

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000556

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.00268

Gnomad MID AF: 0.0352

Gnomad NFE AF: 0.00752

Gnomad OTH AF: 0.00552

GnomAD2 exomes AF: 0.0193 AC: 1175 AN: 60812 AF XY: 0.0191

Gnomad AFR exome AF: 0.00686

Gnomad AMR exome AF: 0.0427

Gnomad ASJ exome AF: 0.0317

Gnomad EAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.00909 AC: 8952 AN: 984562 Hom.: 1778 AF XY: 0.0104 AC XY: 4912 AN XY: 472572

African (AFR) AF: 0.00184 AC: 33 AN: 17932

American (AMR) AF: 0.0298 AC: 191 AN: 6420

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 395 AN: 11504

East Asian (EAS) AF: 0.000484 AC: 7 AN: 14456

South Asian (SAS) AF: 0.0476 AC: 1473 AN: 30970

European-Finnish (FIN) AF: 0.00849 AC: 110 AN: 12956

Middle Eastern (MID) AF: 0.0165 AC: 47 AN: 2840

European-Non Finnish (NFE) AF: 0.00742 AC: 6327 AN: 852722

Other (OTH) AF: 0.0106 AC: 369 AN: 34762

GnomAD4 genome AF: 0.00524 AC: 640 AN: 122078 Hom.: 3 Cov.: 0 AF XY: 0.00473 AC XY: 282 AN XY: 59662

African (AFR) AF: 0.00101 AC: 36 AN: 35516

American (AMR) AF: 0.00593 AC: 76 AN: 12826

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 36 AN: 2964

East Asian (EAS) AF: 0.000558 AC: 2 AN: 3586

South Asian (SAS) AF: 0.0130 AC: 47 AN: 3616

European-Finnish (FIN) AF: 0.00268 AC: 17 AN: 6340

Middle Eastern (MID) AF: 0.0290 AC: 4 AN: 138

European-Non Finnish (NFE) AF: 0.00752 AC: 412 AN: 54764

Other (OTH) AF: 0.00608 AC: 10 AN: 1646

Alfa AF: 0.00254 Hom.: 118

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=191/9	polymorphism (auto)

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;