X-137566740-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003413.4(ZIC3):c.49G>T(p.Gly17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,190,354 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,091 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., 65 hem., cov: 24)
  • Exomes 𝑓: 0.0031 (7 hom. 1026 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13
• Conservation: PhyloP100: 1.85

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077534616).
• BP6: Variant X-137566740-G-T is Benign according to our data. Variant chrX-137566740-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 190129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-137566740-G-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 65 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.49G>T	p.Gly17Cys	missense_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.49G>T	p.Gly17Cys	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.49G>T	p.Gly17Cys	missense_variant	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.49G>T	p.Gly17Cys	missense_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 227 AN: 113102 Hom.: 0 Cov.: 24 AF XY: 0.00184 AC XY: 65 AN XY: 35250

Gnomad AFR AF: 0.000320

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.000830

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00463

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00328

GnomAD3 exomes AF: 0.00259 AC: 366 AN: 141061 Hom.: 1 AF XY: 0.00239 AC XY: 103 AN XY: 43075

Gnomad AFR exome AF: 0.000408

Gnomad AMR exome AF: 0.000998

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000128

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00311 AC: 3350 AN: 1077197 Hom.: 7 Cov.: 32 AF XY: 0.00293 AC XY: 1026 AN XY: 349763

Gnomad4 AFR exome AF: 0.000421

Gnomad4 AMR exome AF: 0.000943

Gnomad4 ASJ exome AF: 0.00147

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000777

Gnomad4 FIN exome AF: 0.00515

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00201 AC: 227 AN: 113157 Hom.: 0 Cov.: 24 AF XY: 0.00184 AC XY: 65 AN XY: 35315

Gnomad4 AFR AF: 0.000320

Gnomad4 AMR AF: 0.000829

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00463

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00324

Alfa AF: 0.00297 Hom.: 86

Bravo AF: 0.00164

ESP6500AA AF: 0.00131 AC: 5

ESP6500EA AF: 0.00388 AC: 26

ExAC AF: 0.00268 AC: 318

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ZIC3: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26294094, 19933292, 24123890, 23427188) -

Heterotaxy, visceral, 1, X-linked Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of X-linked recessive Congenital heart defects, nonsyndromic, 1 (MIM#306955). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

VACTERL association, X-linked, with or without hydrocephalus Pathogenic:1 Benign:1

Pathogenic, flagged submission	research	Reutter Lab, Institute of Human Genetics, University Hospital Bonn	Jan 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 02, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1% frequency and 26 hemizygotes in the European population in ExAC -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital heart defects 1, nonsyndromic, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.48
MVP		0.65
MPC		2.4
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.51
gMVP		0.64

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: rs147232392; hg19: chrX-136648899;