3-147390947-C-T

Position:

• chr3-147390947-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032153.6(ZIC4):​c.988G>A​(p.Ala330Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,457,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ZIC4 NM_032153.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.253

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052452475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIC4	NM_032153.6	c.988G>A	p.Ala330Thr	missense_variant	4/5	ENST00000383075.8	NP_115529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIC4	ENST00000383075.8	c.988G>A	p.Ala330Thr	missense_variant	4/5	1	NM_032153.6	ENSP00000372553	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1457720 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 724950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ZIC4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 380 of the ZIC4 protein (p.Ala380Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T;.;.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.70	.;T;T;.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.052	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N;.;.;N;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.040	N;N;N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.44	T;T;T;T;T;T
Sift4G	Benign	0.75	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;B;B;.
Vest4		0.018
MutPred		0.23		Gain of glycosylation at A330 (P = 0.0106);.;.;Gain of glycosylation at A330 (P = 0.0106);Gain of glycosylation at A330 (P = 0.0106);.;
MVP		0.35
MPC		0.49
ClinPred		0.091	T
GERP RS		3.1
Varity_R		0.037
gMVP		0.44

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: rs775064886; hg19: chr3-147108734;