Genetic Variant NM_033132.5:c.1170_1190delGCCGCCGCCGCCGCCGCCGCC (chr13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

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

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant 13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chr13-99970413-TGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.1170_1190delGCCGCCGCCGCCGCCGCCGCC	p.Pro391_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	NP_149123.3	Q96T25
	ZIC5	NR_146224.1		n.1476_1496delGCCGCCGCCGCCGCCGCCGCC		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZIC5	ENST00000267294.5	TSL:1 MANE Select	c.1170_1190delGCCGCCGCCGCCGCCGCCGCC	p.Pro391_Pro397del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000267294.4	Q96T25
ENSG00000297638	ENST00000749511.1		n.135+301_135+321delGGCGGCGGCGGCGGCGGCGGC		intron	N/A
ENSG00000297638	ENST00000749512.1		n.104+295_104+315delGGCGGCGGCGGCGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00525

AC:

640

AN:

121978

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.00184

AC:

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:

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:

AN:

2840

European-Non Finnish (NFE)

AF:

0.00742

AC:

6327

AN:

852722

Other (OTH)

AF:

0.0106

AC:

369

AN:

34762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.616

Heterozygous variant carriers

181

362

544

725

906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.00524

AC:

640

AN:

122078

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

282

AN XY:

59662

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

35516

American (AMR)

AF:

0.00593

AC:

AN:

12826

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

2964

East Asian (EAS)

AF:

0.000558

AC:

AN:

3586

South Asian (SAS)

AF:

0.0130

AC:

AN:

3616

European-Finnish (FIN)

AF:

0.00268

AC:

AN:

6340

Middle Eastern (MID)

AF:

0.0290

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.00752

AC:

412

AN:

54764

Other (OTH)

AF:

0.00608

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00254

Hom.:

118

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=191/9

polymorphism (auto)

(source)

Splicing

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

Publications

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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