chr3-147390970-G-A

Position:

• chr3-147390970-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032153.6(ZIC4):​c.965C>T​(p.Ser322Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00242 in 1,612,224 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S322W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (81 hom.)
• Consequence: ZIC4 NM_032153.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.99

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004215896).
• BP6: Variant 3-147390970-G-A is Benign according to our data. Variant chr3-147390970-G-A is described in ClinVar as [Benign]. Clinvar id is 778289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00244 (3565/1459886) while in subpopulation AMR AF= 0.0435 (1942/44638). AF 95% confidence interval is 0.0419. There are 81 homozygotes in gnomad4_exome. There are 1601 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC4	NM_032153.6	c.965C>T	p.Ser322Leu	missense_variant	4/5	ENST00000383075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC4	ENST00000383075.8	c.965C>T	p.Ser322Leu	missense_variant	4/5	1	NM_032153.6	P2

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 337 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00851 AC: 2062 AN: 242190 Hom.: 48 AF XY: 0.00640 AC XY: 849 AN XY: 132574

Gnomad AFR exome AF: 0.000275

Gnomad AMR exome AF: 0.0488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0194

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000830

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00244 AC: 3565 AN: 1459886 Hom.: 81 Cov.: 31 AF XY: 0.00220 AC XY: 1601 AN XY: 726160

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0435

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0370

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74486

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00113 Hom.: 2

Bravo AF: 0.00457

ESP6500AA AF: 0.000491 AC: 2

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00670 AC: 808

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;.;D;D
MetaRNN	Benign	0.0042	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;.;M;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N;N;N;D
REVEL	Benign	0.095
Sift	Uncertain	0.026	D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D;D
Polyphen		0.38	B;.;.;B;B;.
Vest4		0.39
MVP		0.60
MPC		1.2
ClinPred		0.068	T
GERP RS		5.2
Varity_R		0.22
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs183217537; hg19: chr3-147108757; COSMIC: COSV67173737; COSMIC: COSV67173737;