X-137566825-ACGCCGCCGCCGCCGC-ACGCCGC

Variant names:

• chrX-137566825-ACGCCGCCGC-A
• rs748325646
• NM_003413.4:c.153_161delCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_003413.4(ZIC3):​c.153_161delCGCCGCCGC​(p.Ala52_Ala54del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,160,670 control chromosomes in the GnomAD database, including 1 homozygotes. There are 229 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 23 hem., cov: 24)
  • Exomes 𝑓: 0.00066 (1 hom. 206 hem.)
• Consequence: ZIC3 NM_003413.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter U:3 B:2
• 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003413.4
• BP6: Variant X-137566825-ACGCCGCCGC-A is Benign according to our data. Variant chrX-137566825-ACGCCGCCGC-A is described in ClinVar as Benign. ClinVar VariationId is 464970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 23 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.153_161delCGCCGCCGC	p.Ala52_Ala54del	disruptive_inframe_deletion	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.153_161delCGCCGCCGC	p.Ala52_Ala54del	disruptive_inframe_deletion	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.153_161delCGCCGCCGC	p.Ala52_Ala54del	disruptive_inframe_deletion	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.153_161delCGCCGCCGC	p.Ala52_Ala54del	disruptive_inframe_deletion	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.153_161delCGCCGCCGC	p.Ala52_Ala54del	disruptive_inframe_deletion	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.000734 AC: 82 AN: 111758 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00171

Gnomad SAS AF: 0.000742

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000605

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000829 AC: 80 AN: 96477 AF XY: 0.000921

Gnomad AFR exome AF: 0.000793

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00330

Gnomad FIN exome AF: 0.000162

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000664 AC: 696 AN: 1048869 Hom.: 1 AF XY: 0.000603 AC XY: 206 AN XY: 341511

African (AFR) AF: 0.000920 AC: 23 AN: 25002

American (AMR) AF: 0.000780 AC: 22 AN: 28191

Ashkenazi Jewish (ASJ) AF: 0.0000536 AC: 1 AN: 18644

East Asian (EAS) AF: 0.00326 AC: 89 AN: 27323

South Asian (SAS) AF: 0.000381 AC: 19 AN: 49918

European-Finnish (FIN) AF: 0.000128 AC: 4 AN: 31347

Middle Eastern (MID) AF: 0.00102 AC: 4 AN: 3940

European-Non Finnish (NFE) AF: 0.000621 AC: 509 AN: 820175

Other (OTH) AF: 0.000564 AC: 25 AN: 44329

GnomAD4 genome AF: 0.000725 AC: 81 AN: 111801 Hom.: 0 Cov.: 24 AF XY: 0.000673 AC XY: 23 AN XY: 34197

African (AFR) AF: 0.000938 AC: 29 AN: 30920

American (AMR) AF: 0.000933 AC: 10 AN: 10723

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

East Asian (EAS) AF: 0.00172 AC: 6 AN: 3496

South Asian (SAS) AF: 0.000744 AC: 2 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: 0.000605 AC: 32 AN: 52915

Other (OTH) AF: 0.00132 AC: 2 AN: 1517

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000880

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	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		=197/3	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;