NM_032153.6:c.966G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_032153.6(ZIC4):c.966G>C(p.Ser322Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,612,086 control chromosomes in the GnomAD database, including 1,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S322S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.030 ( 108 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1281 hom. )

Consequence

ZIC4
NM_032153.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.690

Publications

3 publications found

Variant links:

Genes affected

ZIC4 (HGNC:20393): (Zic family member 4) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development, and have been associated with X-linked visceral heterotaxy and holoprosencephaly type 5. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 1, a related family member on chromosome 3. Heterozygous deletion of these linked genes is involved in Dandy-Walker malformation, which is a congenital cerebellar malformation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Dec 2009]

ZIC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 3-147390969-C-G is Benign according to our data. Variant chr3-147390969-C-G is described in ClinVar as Benign. ClinVar VariationId is 130789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.69 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0295 (4496/152334) while in subpopulation NFE AF = 0.0478 (3251/68032). AF 95% confidence interval is 0.0464. There are 108 homozygotes in GnomAd4. There are 2091 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 108 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC4	NM_032153.6 link	c.966G>C	p.Ser322Ser	synonymous_variant	Exon 4 of 5	ENST00000383075.8	NP_115529.2	Q8N9L1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC4	ENST00000383075.8 link	c.966G>C	p.Ser322Ser	synonymous_variant	Exon 4 of 5	1	NM_032153.6	ENSP00000372553.3		Q8N9L1-1

Frequencies

GnomAD3 genomes

AF:

0.0296

AC:

4499

AN:

152216

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00839

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0373

GnomAD2 exomes

AF:

0.0299

AC:

7231

AN:

241788

AF XY:

0.0309

show subpopulations

Gnomad AFR exome

AF:

0.00767

Gnomad AMR exome

AF:

0.0197

Gnomad ASJ exome

AF:

0.0330

Gnomad EAS exome

AF:

0.0000565

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.0482

Gnomad OTH exome

AF:

0.0364

GnomAD4 exome

AF:

0.0388

AC:

56595

AN:

1459752

Hom.:

1281

Cov.:

AF XY:

0.0383

AC XY:

27814

AN XY:

726086

show subpopulations

African (AFR)

AF:

0.00652

AC:

218

AN:

33452

American (AMR)

AF:

0.0214

AC:

956

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

848

AN:

26054

East Asian (EAS)

AF:

0.000101

AC:

AN:

39674

South Asian (SAS)

AF:

0.0118

AC:

1013

AN:

86140

European-Finnish (FIN)

AF:

0.0180

AC:

948

AN:

52542

Middle Eastern (MID)

AF:

0.0483

AC:

276

AN:

5716

European-Non Finnish (NFE)

AF:

0.0451

AC:

50163

AN:

1111212

Other (OTH)

AF:

0.0360

AC:

2169

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

3491

6981

10472

13962

17453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1774

3548

5322

7096

8870

<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:

0.0295

AC:

4496

AN:

152334

Hom.:

108

Cov.:

AF XY:

0.0281

AC XY:

2091

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00837

AC:

348

AN:

41582

American (AMR)

AF:

0.0297

AC:

455

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5162

South Asian (SAS)

AF:

0.0118

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10630

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0478

AC:

3251

AN:

68032

Other (OTH)

AF:

0.0369

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

232

464

697

929

1161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0257

Hom.:

Bravo

AF:

0.0294

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0476

EpiControl

AF:

0.0507

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

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

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.9

(source)

DANN

Benign

0.83

PhyloP100

-0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over