chr3-147391142-T-G

Position:

• chr3-147391142-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032153.6(ZIC4):​c.793A>C​(p.Thr265Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T265M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZIC4 NM_032153.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.811

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37274554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC4	NM_032153.6	c.793A>C	p.Thr265Pro	missense_variant	4/5	ENST00000383075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC4	ENST00000383075.8	c.793A>C	p.Thr265Pro	missense_variant	4/5	1	NM_032153.6	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.943A>C (p.T315P) alteration is located in exon 4 (coding exon 4) of the ZIC4 gene. This alteration results from a A to C substitution at nucleotide position 943, causing the threonine (T) at amino acid position 315 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;T;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T;T;.;T;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.36	N;.;.;N;N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.21	T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T
Polyphen		0.76	P;.;.;P;P;.
Vest4		0.23
MutPred		0.35		Gain of catalytic residue at T265 (P = 2e-04);.;.;Gain of catalytic residue at T265 (P = 2e-04);Gain of catalytic residue at T265 (P = 2e-04);.;
MVP		0.76
MPC		1.6
ClinPred		0.72	D
GERP RS		4.8
Varity_R		0.46
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-147108929;