X-137566710-G-C

Variant names:

• chrX-137566710-G-C
• rs763534805
• NM_003413.4:c.19G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_003413.4(ZIC3):​c.19G>C​(p.Gly7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,085,516 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000016 (0 hom. 10 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.29

Genes affected

ZIC3 (HGNC:12874): (Zic family member 3) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. This nuclear protein probably functions as a transcription factor in early stages of left-right body axis formation. Mutations in this gene cause X-linked visceral heterotaxy, which includes congenital heart disease and left-right axis defects in organs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP5: Variant X-137566710-G-C is Pathogenic according to our data. Variant chrX-137566710-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418553.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16089576). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4	c.19G>C	p.Gly7Arg	missense_variant	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1	c.19G>C	p.Gly7Arg	missense_variant	Exon 1 of 3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC3	ENST00000287538.10	c.19G>C	p.Gly7Arg	missense_variant	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5
ZIC3	ENST00000370606.3	c.19G>C	p.Gly7Arg	missense_variant	Exon 1 of 3	5		ENSP00000359638.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000652 AC: 1 AN: 153469 Hom.: 0 AF XY: 0.0000209 AC XY: 1 AN XY: 47917

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 17 AN: 1085516 Hom.: 0 Cov.: 32 AF XY: 0.0000282 AC XY: 10 AN XY: 354398

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: 0.0000191

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2013

The Gly7Arg variant in the ZIC3 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. Gly7Arg results in a non-conservative amino acid substitution of a non-polar Glycine residue with a positively charged Arginine residue at a position that is conserved across species. In silico analysis predicts Gly7Arg is probably damaging to the protein structure/function. A variant affecting a nearby residue (Gly17Cys) has been reported in HGMD in association with a cardiac malformation (Stenson P et al., 2009), further supporting the functional importance of this region of the protein. Furthermore, the Gly7Arg variant was not observed in approximately 5,300 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. In summary, while Gly7Arg is a good candidate for a pathogenic variant, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The pathogenic role for this variant would be further supported if it occurred de novo in this individual or if it co-segregates with the disease phenotype in this family. -

Heterotaxy, visceral, 1, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 7 of the ZIC3 protein (p.Gly7Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has not been reported in the literature in individuals with ZIC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 418553). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;.
Vest4		0.21
MutPred		0.14		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.16
MPC		2.2
ClinPred		0.70	D
GERP RS		3.2
Varity_R		0.40
gMVP		0.54

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: rs763534805; hg19: chrX-136648869;