NM_003413.4:c.159_161dupCGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_003413.4(ZIC3):​c.159_161dupCGC​(p.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 0.00409 in 1,160,230 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,071 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A54A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., 59 hem., cov: 24)
Exomes 𝑓: 0.0043 ( 9 hom. 1012 hem. )

Consequence

ZIC3
NM_003413.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

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 -6 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_003413.4
BP6
Variant X-137566825-A-ACGC is Benign according to our data. Variant chrX-137566825-A-ACGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259047.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High Hemizygotes in GnomAd4 at 59 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZIC3NM_003413.4 linkc.159_161dupCGC p.Ala54dup disruptive_inframe_insertion Exon 1 of 3 ENST00000287538.10 NP_003404.1
ZIC3NM_001330661.1 linkc.159_161dupCGC p.Ala54dup disruptive_inframe_insertion 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.159_161dupCGC p.Ala54dup disruptive_inframe_insertion Exon 1 of 3 1 NM_003413.4 ENSP00000287538.5 O60481-1
ZIC3ENST00000370606.3 linkc.159_161dupCGC p.Ala54dup disruptive_inframe_insertion Exon 1 of 3 5 ENSP00000359638.3 O60481-2
LINC02931ENST00000786828.1 linkn.130+2246_130+2248dupGCG intron_variant Intron 1 of 5

Frequencies

GnomAD3 genomes
AF:
0.00247
AC:
276
AN:
111757
Hom.:
1
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.000972
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000560
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00222
Gnomad FIN
AF:
0.00117
Gnomad MID
AF:
0.00422
Gnomad NFE
AF:
0.00418
Gnomad OTH
AF:
0.00334
GnomAD2 exomes
AF:
0.00205
AC:
198
AN:
96477
AF XY:
0.00157
show subpopulations
Gnomad AFR exome
AF:
0.000396
Gnomad AMR exome
AF:
0.000647
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000527
Gnomad FIN exome
AF:
0.000810
Gnomad NFE exome
AF:
0.00408
Gnomad OTH exome
AF:
0.00170
GnomAD4 exome
AF:
0.00426
AC:
4468
AN:
1048430
Hom.:
9
Cov.:
33
AF XY:
0.00297
AC XY:
1012
AN XY:
341090
show subpopulations
African (AFR)
AF:
0.000880
AC:
22
AN:
25000
American (AMR)
AF:
0.000781
AC:
22
AN:
28187
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
18643
East Asian (EAS)
AF:
0.000293
AC:
8
AN:
27323
South Asian (SAS)
AF:
0.00182
AC:
91
AN:
49903
European-Finnish (FIN)
AF:
0.00112
AC:
35
AN:
31247
Middle Eastern (MID)
AF:
0.00203
AC:
8
AN:
3940
European-Non Finnish (NFE)
AF:
0.00505
AC:
4144
AN:
819869
Other (OTH)
AF:
0.00311
AC:
138
AN:
44318
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.467
Heterozygous variant carriers
0
245
490
735
980
1225
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
168
336
504
672
840
<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:
0.00247
AC:
276
AN:
111800
Hom.:
1
Cov.:
24
AF XY:
0.00173
AC XY:
59
AN XY:
34198
show subpopulations
African (AFR)
AF:
0.000970
AC:
30
AN:
30921
American (AMR)
AF:
0.000559
AC:
6
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:
0.00223
AC:
6
AN:
2687
European-Finnish (FIN)
AF:
0.00117
AC:
7
AN:
6005
Middle Eastern (MID)
AF:
0.00463
AC:
1
AN:
216
European-Non Finnish (NFE)
AF:
0.00420
AC:
222
AN:
52915
Other (OTH)
AF:
0.00264
AC:
4
AN:
1517
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
12
25
37
50
62
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.00124
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Nov 02, 2015
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Heterotaxy, visceral, 1, X-linked Benign:1
Jan 08, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ZIC3-related disorder Benign:1
Nov 21, 2019
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 (auto)

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; COSMIC: COSV54975823; COSMIC: COSV54975823; API