chrX-137566825-A-ACGCCGC

Variant names:

• chrX-137566825-A-ACGCCGC
• rs748325646
• NM_003413.4:c.156_161dupCGCCGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_003413.4(ZIC3):​c.156_161dupCGCCGC​(p.Ala53_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 0.0015 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 (★). Synonymous variant affecting the same amino acid position (i.e. A54A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (13 hom., 146 hem., cov: 24)
  • Exomes 𝑓: 0.0014 (11 hom. 344 hem.)
• Consequence: ZIC3 NM_003413.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.41
• Publications: 1 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BS2: High Homozygotes in GnomAd4 at 13 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	NM_003413.4	MANE Select	c.156_161dupCGCCGC	p.Ala53_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.156_161dupCGCCGC	p.Ala53_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	NP_001317590.1	O60481-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.156_161dupCGCCGC	p.Ala53_Ala54dup	disruptive_inframe_insertion	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.156_161dupCGCCGC	p.Ala53_Ala54dup	disruptive_inframe_insertion	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.156_161dupCGCCGC	p.Ala53_Ala54dup	disruptive_inframe_insertion	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 317 AN: 111751 Hom.: 13 Cov.: 24

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

GnomAD2 exomes AF: 0.00223 AC: 215 AN: 96477 AF XY: 0.00138

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 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.: 11 Cov.: 33 AF XY: 0.00101 AC XY: 344 AN XY: 341378

African (AFR) AF: 0.0000800 AC: 2 AN: 25002

American (AMR) AF: 0.000248 AC: 7 AN: 28191

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

East Asian (EAS) AF: 0.000220 AC: 6 AN: 27320

South Asian (SAS) AF: 0.0000200 AC: 1 AN: 49900

European-Finnish (FIN) AF: 0.0349 AC: 1092 AN: 31253

Middle Eastern (MID) AF: 0.000761 AC: 3 AN: 3940

European-Non Finnish (NFE) AF: 0.000329 AC: 270 AN: 820158

Other (OTH) AF: 0.000948 AC: 42 AN: 44326

GnomAD4 genome AF: 0.00284 AC: 317 AN: 111794 Hom.: 13 Cov.: 24 AF XY: 0.00427 AC XY: 146 AN XY: 34190

African (AFR) AF: 0.0000970 AC: 3 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: 0.00 AC: 0 AN: 2687

European-Finnish (FIN) AF: 0.0453 AC: 272 AN: 5999

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

European-Non Finnish (NFE) AF: 0.000775 AC: 41 AN: 52915

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00131 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Heterotaxy, visceral, 1, X-linked (1)
-	-	1	ZIC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=72/28	polymorphism (auto)

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;