X-137566788-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003413.4(ZIC3):​c.97G>T​(p.Ala33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,178,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 8 hem., cov: 25)
Exomes 𝑓: 0.000011 ( 0 hom. 3 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.766
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.07871276).
BS2
High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZIC3NM_003413.4 linkuse as main transcriptc.97G>T p.Ala33Ser missense_variant 1/3 ENST00000287538.10 NP_003404.1
ZIC3NM_001330661.1 linkuse as main transcriptc.97G>T p.Ala33Ser missense_variant 1/3 NP_001317590.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZIC3ENST00000287538.10 linkuse as main transcriptc.97G>T p.Ala33Ser missense_variant 1/31 NM_003413.4 ENSP00000287538 P1O60481-1
ZIC3ENST00000370606.3 linkuse as main transcriptc.97G>T p.Ala33Ser missense_variant 1/35 ENSP00000359638 O60481-2

Frequencies

GnomAD3 genomes
AF:
0.000186
AC:
21
AN:
113197
Hom.:
0
Cov.:
25
AF XY:
0.000226
AC XY:
8
AN XY:
35337
show subpopulations
Gnomad AFR
AF:
0.000640
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000921
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000162
AC:
2
AN:
123398
Hom.:
0
AF XY:
0.0000258
AC XY:
1
AN XY:
38764
show subpopulations
Gnomad AFR exome
AF:
0.000254
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000113
AC:
12
AN:
1065512
Hom.:
0
Cov.:
32
AF XY:
0.00000867
AC XY:
3
AN XY:
345840
show subpopulations
Gnomad4 AFR exome
AF:
0.000232
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000242
Gnomad4 OTH exome
AF:
0.0000890
GnomAD4 genome
AF:
0.000186
AC:
21
AN:
113197
Hom.:
0
Cov.:
25
AF XY:
0.000226
AC XY:
8
AN XY:
35337
show subpopulations
Gnomad4 AFR
AF:
0.000640
Gnomad4 AMR
AF:
0.0000921
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000200
ExAC
AF:
0.0000176
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 06, 2021This sequence change replaces alanine with serine at codon 33 of the ZIC3 protein (p.Ala33Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with ZIC3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 13, 2023The c.97G>T (p.A33S) alteration is located in exon 1 (coding exon 1) of the ZIC3 gene. This alteration results from a G to T substitution at nucleotide position 97, causing the alanine (A) at amino acid position 33 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.84
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.18
T;.
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.74
T;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.079
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.65
N;N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.25
N;N
REVEL
Benign
0.042
Sift
Benign
0.21
T;T
Sift4G
Benign
0.64
T;T
Polyphen
0.67
P;.
Vest4
0.20
MVP
0.23
MPC
1.2
ClinPred
0.052
T
GERP RS
3.2
Varity_R
0.12
gMVP
0.10

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746833203; hg19: chrX-136648947; COSMIC: COSV54977378; COSMIC: COSV54977378; API