Variant chrX-137566825-A-ACGCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3BS2

The NM_003413.4(ZIC3):c.156_161dup(p.Ala54_Ala55dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,160,528 control chromosomes in the GnomAD database, including 24 homozygotes. There are 490 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0028 ( 13 hom., 146 hem., cov: 24)

Exomes 𝑓: 0.0014 ( 11 hom. 344 hem. )

Consequence

ZIC3
NM_003413.4 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 1.41

Variant links:

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]

ZIC3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003413.4

BS2

High Homozygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4 linkuse as main transcript	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3	ENST00000287538.10
ZIC3	NM_001330661.1 linkuse as main transcript	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10 linkuse as main transcript	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3	1	NM_003413.4	P1	O60481-1
ZIC3	ENST00000370606.3 linkuse as main transcript	c.156_161dup	p.Ala54_Ala55dup	inframe_insertion	1/3	5			O60481-2

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

317

AN:

111751

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

146

AN XY:

34137

show subpopulations

Gnomad AFR

AF:

0.0000972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000934

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0453

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000775

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00223

AC:

215

AN:

96477

Hom.:

AF XY:

0.00138

AC XY:

AN XY:

32583

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000270

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000264

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.000376

Gnomad OTH exome

AF:

0.00136

GnomAD4 exome

AF:

0.00136

AC:

1423

AN:

1048734

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

344

AN XY:

341378

show subpopulations

Gnomad4 AFR exome

AF:

0.0000800

Gnomad4 AMR exome

AF:

0.000248

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000220

Gnomad4 SAS exome

AF:

0.0000200

Gnomad4 FIN exome

AF:

0.0349

Gnomad4 NFE exome

AF:

0.000329

Gnomad4 OTH exome

AF:

0.000948

GnomAD4 genome

AF:

0.00284

AC:

317

AN:

111794

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

146

AN XY:

34190

show subpopulations

Gnomad4 AFR

AF:

0.0000970

Gnomad4 AMR

AF:

0.0000932

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0453

Gnomad4 NFE

AF:

0.000775

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 17, 2022

This variant, c.156_161dup, results in the insertion of 2 amino acid(s) of the ZIC3 protein (p.Ala54_Ala55dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ZIC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 411872). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

ZIC3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over