3-147403964-C-T

Position:

chr3-147403964-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 links:

ZIC1 (HGNC:):

ZIC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIC4	NM_032153.6 linkuse as main transcript	c.-15-1152G>A		intron_variant		ENST00000383075.8	NP_115529.2	Q8N9L1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIC4	ENST00000383075.8 linkuse as main transcript	c.-15-1152G>A		intron_variant		1	NM_032153.6	ENSP00000372553.3		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

GnomAD3 exomes

AF:

0.172

AC:

23758

AN:

138504

Hom.:

2362

AF XY:

0.174

AC XY:

12918

AN XY:

74318

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 SAS exome

AF:

0.136

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

Gnomad4 AFR exome

AF:

0.114

Gnomad4 AMR exome

AF:

0.132

Gnomad4 ASJ exome

AF:

0.179

Gnomad4 EAS exome

AF:

0.0830

Gnomad4 SAS exome

AF:

0.135

Gnomad4 FIN exome

AF:

0.173

Gnomad4 NFE exome

AF:

0.233

Gnomad4 OTH exome

AF:

0.198

GnomAD4 genome

AF:

0.178

AC:

27149

AN:

152148

Hom.:

2651

Cov.:

AF XY:

0.175

AC XY:

13026

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.119

Gnomad4 AMR

AF:

0.177

Gnomad4 ASJ

AF:

0.176

Gnomad4 EAS

AF:

0.0622

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.161

Gnomad4 NFE

AF:

0.230

Gnomad4 OTH

AF:

0.204

Alfa

AF:

0.208

Hom.:

4683

Bravo

AF:

0.176

Asia WGS

AF:

0.102

AC:

355

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Benign

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over