dbSNP rs6766244: ZIC4:c.-15-1152G>A (chr3-147403964-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001168378.1(ZIC4):c.135G>A(p.Lys45Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,536,262 control chromosomes in the GnomAD database, including 35,870 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2651 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33219 hom. )

Consequence

ZIC4
NM_001168378.1 splice_region, synonymous

Scores

Splicing: ADA: 0.6585

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.31

Publications

9 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:

ZIC1 (HGNC:12872): (Zic family member 1) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. Members of this family are important during development. Aberrant expression of this gene is seen in medulloblastoma, a childhood brain tumor. This gene is closely linked to the gene encoding zinc finger protein of the cerebellum 4, a related family member on chromosome 3. This gene encodes a transcription factor that can bind and transactivate the apolipoprotein E gene. [provided by RefSeq, Jul 2008]

ZIC1 Gene-Disease associations (from GenCC):

craniosynostosis 6
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
structural brain anomalies with impaired intellectual development and craniosynostosis
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
isolated brachycephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated oxycephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated plagiocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Dandy-Walker syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ZIC1 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=-0.19).

BP6

Variant 3-147403964-C-T is Benign according to our data. Variant chr3-147403964-C-T is described in ClinVar as Benign. ClinVar VariationId is 403620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168378.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZIC4	NM_032153.6	MANE Select	c.-15-1152G>A		intron	N/A	NP_115529.2
ZIC4	NM_001168378.1		c.135G>A	p.Lys45Lys	splice_region synonymous	Exon 1 of 5	NP_001161850.1	Q8N9L1-3
ZIC4	NM_001168379.2		c.100-1152G>A		intron	N/A	NP_001161851.1	Q8N9L1-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ZIC4	ENST00000383075.8	TSL:1 MANE Select	c.-15-1152G>A	intron	N/A	ENSP00000372553.3	Q8N9L1-1
ZIC4	ENST00000462748.6	TSL:1	c.-15-1152G>A	intron	N/A	ENSP00000420627.2	C9JD04
ZIC4	ENST00000484399.5	TSL:2	c.-16G>A	splice_region	Exon 1 of 5	ENSP00000417855.1	Q8N9L1-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27144

AN:

152030

Hom.:

2650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.176

Gnomad EAS

AF:

0.0618

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.206

GnomAD2 exomes

AF:

0.172

AC:

23758

AN:

138504

AF XY:

0.174

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.0540

Gnomad FIN exome

AF:

0.181

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.204

GnomAD4 exome

AF:

0.214

AC:

295935

AN:

1384114

Hom.:

33219

Cov.:

AF XY:

0.212

AC XY:

144618

AN XY:

683002

show subpopulations

African (AFR)

AF:

0.114

AC:

3607

AN:

31572

American (AMR)

AF:

0.132

AC:

4707

AN:

35652

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4503

AN:

25144

East Asian (EAS)

AF:

0.0830

AC:

2963

AN:

35714

South Asian (SAS)

AF:

0.135

AC:

10645

AN:

79142

European-Finnish (FIN)

AF:

0.173

AC:

6049

AN:

34946

Middle Eastern (MID)

AF:

0.205

AC:

1166

AN:

5694

European-Non Finnish (NFE)

AF:

0.233

AC:

250861

AN:

1078372

Other (OTH)

AF:

0.198

AC:

11434

AN:

57878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

11118

22235

33353

44470

55588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8580

17160

25740

34320

42900

<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:

0.178

AC:

27149

AN:

152148

Hom.:

2651

Cov.:

AF XY:

0.175

AC XY:

13026

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.119

AC:

4953

AN:

41504

American (AMR)

AF:

0.177

AC:

2702

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

609

AN:

3470

East Asian (EAS)

AF:

0.0622

AC:

322

AN:

5180

South Asian (SAS)

AF:

0.126

AC:

609

AN:

4822

European-Finnish (FIN)

AF:

0.161

AC:

1702

AN:

10582

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15669

AN:

67988

Other (OTH)

AF:

0.204

AC:

431

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1136

2273

3409

4546

5682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.208

Hom.:

10277

Bravo

AF:

0.176

Asia WGS

AF:

0.102

AC:

355

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Benign

0.95

PhyloP100

3.3

PromoterAI

-0.040

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.66

dbscSNV1_RF

Benign

0.26

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over