3-147390969-C-G

Position:

• chr3-147390969-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_032153.6(ZIC4):​c.966G>C​(p.Ser322=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.690

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 108 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC4	NM_032153.6	c.966G>C	p.Ser322=	synonymous_variant	4/5	ENST00000383075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC4	ENST00000383075.8	c.966G>C	p.Ser322=	synonymous_variant	4/5	1	NM_032153.6	P2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4499 AN: 152216 Hom.: 108 Cov.: 33

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

GnomAD3 exomes AF: 0.0299 AC: 7231 AN: 241788 Hom.: 149 AF XY: 0.0309 AC XY: 4092 AN XY: 132390

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 SAS exome AF: 0.0112

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.: 31 AF XY: 0.0383 AC XY: 27814 AN XY: 726086

Gnomad4 AFR exome AF: 0.00652

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0325

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0451

Gnomad4 OTH exome AF: 0.0360

GnomAD4 genome AF: 0.0295 AC: 4496 AN: 152334 Hom.: 108 Cov.: 33 AF XY: 0.0281 AC XY: 2091 AN XY: 74486

Gnomad4 AFR AF: 0.00837

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0257 Hom.: 19

Bravo AF: 0.0294

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.0476

EpiControl AF: 0.0507

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
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 -

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.9
DANN	Benign	0.83

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

LitVar

Other links and lift over

dbSNP: rs17509456; hg19: chr3-147108756; COSMIC: COSV67172910; COSMIC: COSV67172910;