chr3-147396034-G-C

Position:

• chr3-147396034-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_032153.6(ZIC4):​c.506C>G​(p.Ala169Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,234 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (47 hom.)
• Consequence: ZIC4 NM_032153.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.52

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0090051).
• BP6: Variant 3-147396034-G-C is Benign according to our data. Variant chr3-147396034-G-C is described in ClinVar as [Benign]. Clinvar id is 2038269.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC4	NM_032153.6	c.506C>G	p.Ala169Gly	missense_variant	3/5	ENST00000383075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC4	ENST00000383075.8	c.506C>G	p.Ala169Gly	missense_variant	3/5	1	NM_032153.6	P2

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152234 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00599 AC: 1506 AN: 251324 Hom.: 13 AF XY: 0.00597 AC XY: 811 AN XY: 135902

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0159

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00667 AC: 9750 AN: 1461882 Hom.: 47 Cov.: 32 AF XY: 0.00654 AC XY: 4755 AN XY: 727244

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00272

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.00732

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152352 Hom.: 9 Cov.: 33 AF XY: 0.00675 AC XY: 503 AN XY: 74492

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.00716

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00618 Hom.: 3

Bravo AF: 0.00497

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00631 AC: 766

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00800

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T;T;.;T;T
MetaRNN	Benign	0.0090	T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.33	N;.;.;N;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.037	D;D;D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;T;T;.
Polyphen		0.38	B;.;.;B;B;.
Vest4		0.31
MVP		0.81
MPC		0.53
ClinPred		0.015	T
GERP RS		2.1
Varity_R		0.14
gMVP		0.33

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: rs62001026; hg19: chr3-147113821;