X-137566822-C-G

Position:

chrX-137566822-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003413.4(ZIC3):c.131C>G(p.Thr44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,164,087 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 9 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 1 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.28

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]

ZIC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037341982).

BP6

Variant X-137566822-C-G is Benign according to our data. Variant chrX-137566822-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 367953.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4 linkuse as main transcript	c.131C>G	p.Thr44Ser	missense_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1 linkuse as main transcript	c.131C>G	p.Thr44Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10 linkuse as main transcript	c.131C>G	p.Thr44Ser	missense_variant	1/3	1	NM_003413.4	P1	O60481-1
ZIC3	ENST00000370606.3 linkuse as main transcript	c.131C>G	p.Thr44Ser	missense_variant	1/3	5			O60481-2

Frequencies

GnomAD3 genomes

AF:

0.000142

AC:

AN:

112743

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

AN XY:

34899

show subpopulations

Gnomad AFR

AF:

0.000513

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000382

AC:

AN:

104707

Hom.:

AF XY:

0.00

AC XY:

AN XY:

36269

show subpopulations

Gnomad AFR exome

AF:

0.000535

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:

0.000318

GnomAD4 exome

AF:

0.0000143

AC:

AN:

1051291

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

342261

show subpopulations

Gnomad4 AFR exome

AF:

0.000557

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000142

AC:

AN:

112796

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

34962

show subpopulations

Gnomad4 AFR

AF:

0.000512

Gnomad4 AMR

AF:

0.00

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:

0.0000712

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.0000236

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

VACTERL association, X-linked, with or without hydrocephalus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Congenital heart defects 1, nonsyndromic, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-1.0

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.12

T;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.14

N;N

MutationTaster

Benign

0.98

N;N

PrimateAI

Uncertain

0.79

PROVEAN

Benign

0.27

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.079

MutPred

0.21

Loss of catalytic residue at T44 (P = 0.0032);Loss of catalytic residue at T44 (P = 0.0032);

MVP

0.10

MPC

1.1

ClinPred

0.027

GERP RS

4.2

Varity_R

0.14

gMVP

0.21

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over