chr3-147396245-C-G

Position:

• chr3-147396245-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032153.6(ZIC4):​c.295G>C​(p.Gly99Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,613,552 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (74 hom.)
• Consequence: ZIC4 NM_032153.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.03

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0103960335).
• BP6: Variant 3-147396245-C-G is Benign according to our data. Variant chr3-147396245-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2047054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC4	NM_032153.6	c.295G>C	p.Gly99Arg	missense_variant	3/5	ENST00000383075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC4	ENST00000383075.8	c.295G>C	p.Gly99Arg	missense_variant	3/5	1	NM_032153.6	P2

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1025 AN: 152180 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00929

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00744 AC: 1812 AN: 243616 Hom.: 15 AF XY: 0.00745 AC XY: 990 AN XY: 132942

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00710

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00872

Gnomad OTH exome AF: 0.00791

GnomAD4 exome AF: 0.00810 AC: 11835 AN: 1461254 Hom.: 74 Cov.: 32 AF XY: 0.00823 AC XY: 5985 AN XY: 726942

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00678

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.00846

Gnomad4 OTH exome AF: 0.00769

GnomAD4 genome AF: 0.00674 AC: 1026 AN: 152298 Hom.: 8 Cov.: 33 AF XY: 0.00690 AC XY: 514 AN XY: 74448

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00929

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00703 Hom.: 1

Bravo AF: 0.00545

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00210 AC: 9

ESP6500EA AF: 0.00774 AC: 66

ExAC AF: 0.00687 AC: 831

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00996

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ZIC4: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;.;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;.;.;M;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;.
Polyphen		0.99	D;.;.;D;D;.
Vest4		0.71
MutPred		0.63		Gain of methylation at G99 (P = 0.0178);.;.;Gain of methylation at G99 (P = 0.0178);Gain of methylation at G99 (P = 0.0178);Gain of methylation at G99 (P = 0.0178);
MVP		0.80
MPC		1.6
ClinPred		0.023	T
GERP RS		5.0
Varity_R		0.33
gMVP		0.60

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: rs34676558; hg19: chr3-147114032; COSMIC: COSV67172365; COSMIC: COSV67172365;