3-147403964-C-A

Variant names:

• chr3-147403964-C-A
• rs6766244
• NM_032153.6:c.-15-1152G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001168378.1(ZIC4):​c.135G>T​(p.Lys45Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,384,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K45K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: ZIC4 NM_001168378.1 missense, splice_region
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

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]

ZIC1 Gene-Disease associations (from GenCC):

• craniosynostosis 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• structural brain anomalies with impaired intellectual development and craniosynostosis

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated oxycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dandy-Walker syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001168378.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC4	NM_032153.6	MANE Select	c.-15-1152G>T		intron	N/A	NP_115529.2
	ZIC4	NM_001168378.1		c.135G>T	p.Lys45Asn	missense splice_region	Exon 1 of 5	NP_001161850.1	Q8N9L1-3
	ZIC4	NM_001168379.2		c.100-1152G>T		intron	N/A	NP_001161851.1	Q8N9L1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC4	ENST00000383075.8	TSL:1 MANE Select	c.-15-1152G>T		intron	N/A	ENSP00000372553.3	Q8N9L1-1
	ZIC4	ENST00000462748.6	TSL:1	c.-15-1152G>T		intron	N/A	ENSP00000420627.2	C9JD04
	ZIC4	ENST00000484399.5	TSL:2	c.-16G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000417855.1	Q8N9L1-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1384354 Hom.: 0 Cov.: 32 AF XY: 0.00000732 AC XY: 5 AN XY: 683094

African (AFR) AF: 0.0000317 AC: 1 AN: 31576

American (AMR) AF: 0.00 AC: 0 AN: 35658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25144

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35720

South Asian (SAS) AF: 0.00 AC: 0 AN: 79148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1078568

Other (OTH) AF: 0.00 AC: 0 AN: 57890

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Benign	0.045
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.061
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0060	D
Vest4		0.21
MutPred		0.46		Loss of methylation at K45 (P = 0.0111)
MVP		0.35
MPC		1.3
ClinPred		0.92	D
GERP RS		4.8
PromoterAI		-0.026	Neutral
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Other links and lift over

dbSNP: rs6766244; hg19: chr3-147121751;