X-137566825-ACGCCGCCGCCGCCGC-ACGCCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chrX-137566825-A-ACGCCGCCGC
• rs748325646
• NM_003413.4:c.153_161dupCGCCGCCGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_003413.4(ZIC3):​c.153_161dupCGCCGCCGC​(p.Ala52_Ala54dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,160,653 control chromosomes in the GnomAD database, including 1 homozygotes. There are 59 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. A54A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (1 hom. 57 hem.)
• Consequence: ZIC3 NM_003413.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

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]

LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-A-ACGCCGCCGC is Benign according to our data. Variant chrX-137566825-A-ACGCCGCCGC is described in ClinVar as [Likely_benign]. Clinvar id is 3047546.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4	c.153_161dupCGCCGCCGC	p.Ala52_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1	c.153_161dupCGCCGCCGC	p.Ala52_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC3	ENST00000287538.10	c.153_161dupCGCCGCCGC	p.Ala52_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5
ZIC3	ENST00000370606.3	c.153_161dupCGCCGCCGC	p.Ala52_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	5		ENSP00000359638.3
LINC02931	ENST00000786828.1	n.130+2240_130+2248dupGCGGCGGCG		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0000984 AC: 11 AN: 111761 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000332 AC: 32 AN: 96477 AF XY: 0.000491

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.0000539

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000134 AC: 141 AN: 1048849 Hom.: 1 Cov.: 33 AF XY: 0.000167 AC XY: 57 AN XY: 341491

African (AFR) AF: 0.000200 AC: 5 AN: 25002

American (AMR) AF: 0.0000355 AC: 1 AN: 28191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18644

East Asian (EAS) AF: 0.000183 AC: 5 AN: 27320

South Asian (SAS) AF: 0.00182 AC: 91 AN: 49898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31348

Middle Eastern (MID) AF: 0.000254 AC: 1 AN: 3940

European-Non Finnish (NFE) AF: 0.0000317 AC: 26 AN: 820178

Other (OTH) AF: 0.000271 AC: 12 AN: 44328

GnomAD4 genome AF: 0.0000984 AC: 11 AN: 111804 Hom.: 0 Cov.: 24 AF XY: 0.0000585 AC XY: 2 AN XY: 34200

African (AFR) AF: 0.000162 AC: 5 AN: 30922

American (AMR) AF: 0.0000932 AC: 1 AN: 10724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3496

South Asian (SAS) AF: 0.00112 AC: 3 AN: 2687

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52915

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.0000729 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ZIC3-related disorder Benign:1

Feb 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
PhyloP100		1.4
Mutation Taster		=72/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs748325646; hg19: chrX-136648984;