chrX-137566825-ACGCCGC-A

Variant summary

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

Score: -5 - Likely Benign
-5
-12 -7 -6 -1 0 5 6 9 10 12
BP3BS2

The NM_003413.4(ZIC3):​c.156_161delCGCCGC​(p.Ala53_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 0.0000224 in 1,160,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 24)
Exomes 𝑓: 0.000022 ( 0 hom. 12 hem. )

Consequence

ZIC3
NM_003413.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Publications

0 publications found
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]
LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_003413.4
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZIC3NM_003413.4 linkc.156_161delCGCCGC p.Ala53_Ala54del disruptive_inframe_deletion Exon 1 of 3 ENST00000287538.10 NP_003404.1
ZIC3NM_001330661.1 linkc.156_161delCGCCGC p.Ala53_Ala54del disruptive_inframe_deletion Exon 1 of 3 NP_001317590.1 O60481-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZIC3ENST00000287538.10 linkc.156_161delCGCCGC p.Ala53_Ala54del disruptive_inframe_deletion Exon 1 of 3 1 NM_003413.4 ENSP00000287538.5 O60481-1
ZIC3ENST00000370606.3 linkc.156_161delCGCCGC p.Ala53_Ala54del disruptive_inframe_deletion Exon 1 of 3 5 ENSP00000359638.3 O60481-2
LINC02931ENST00000786828.1 linkn.130+2243_130+2248delGCGGCG intron_variant Intron 1 of 5

Frequencies

GnomAD3 genomes
AF:
0.0000268
AC:
3
AN:
111761
Hom.:
0
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.0000324
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000285
Gnomad SAS
AF:
0.000371
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000415
AC:
4
AN:
96477
AF XY:
0.0000307
show subpopulations
Gnomad AFR exome
AF:
0.000396
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000132
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000340
GnomAD4 exome
AF:
0.0000219
AC:
23
AN:
1048836
Hom.:
0
AF XY:
0.0000351
AC XY:
12
AN XY:
341490
show subpopulations
African (AFR)
AF:
0.0000800
AC:
2
AN:
25002
American (AMR)
AF:
0.00
AC:
0
AN:
28189
Ashkenazi Jewish (ASJ)
AF:
0.0000536
AC:
1
AN:
18644
East Asian (EAS)
AF:
0.0000366
AC:
1
AN:
27322
South Asian (SAS)
AF:
0.0000200
AC:
1
AN:
49910
European-Finnish (FIN)
AF:
0.0000319
AC:
1
AN:
31338
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3940
European-Non Finnish (NFE)
AF:
0.0000195
AC:
16
AN:
820162
Other (OTH)
AF:
0.0000226
AC:
1
AN:
44329
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000268
AC:
3
AN:
111804
Hom.:
0
Cov.:
24
AF XY:
0.0000585
AC XY:
2
AN XY:
34200
show subpopulations
African (AFR)
AF:
0.0000323
AC:
1
AN:
30922
American (AMR)
AF:
0.00
AC:
0
AN:
10724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2640
East Asian (EAS)
AF:
0.000286
AC:
1
AN:
3496
South Asian (SAS)
AF:
0.000372
AC:
1
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:
0.00
AC:
0
AN:
52915
Other (OTH)
AF:
0.00
AC:
0
AN:
1517
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked Uncertain:1
Sep 10, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant, c.156_161delCGCCGC, results in the deletion of 2 amino acid(s) of the ZIC3 protein (p.Ala54_Ala55del), 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 insufficient coverage at this position in the ExAC database. 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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with ZIC3-related disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.4
Mutation Taster
=189/11
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs748325646; hg19: chrX-136648984; API