Variant rs201398331 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003413.4(ZIC3):c.98C>T(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000628 in 1,179,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 3 hem., cov: 25)

Exomes 𝑓: 0.000065 ( 0 hom. 23 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.39

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043459386).

BP6

Variant X-137566789-C-T is Benign according to our data. Variant chrX-137566789-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 533554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIC3	NM_003413.4 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIC3	ENST00000287538.10 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/3	1	NM_003413.4	ENSP00000287538	P1	O60481-1
ZIC3	ENST00000370606.3 linkuse as main transcript	c.98C>T	p.Ala33Val	missense_variant	1/3	5		ENSP00000359638		O60481-2

Frequencies

GnomAD3 genomes

AF:

0.0000441

AC:

AN:

113273

Hom.:

Cov.:

AF XY:

0.0000847

AC XY:

AN XY:

35403

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000921

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000562

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

123646

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

38838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000403

Gnomad SAS exome

AF:

0.000267

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000990

Gnomad OTH exome

AF:

0.000290

GnomAD4 exome

AF:

0.0000647

AC:

AN:

1065759

Hom.:

Cov.:

AF XY:

0.0000665

AC XY:

AN XY:

345993

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000325

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000765

Gnomad4 SAS exome

AF:

0.000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000447

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.0000441

AC:

AN:

113327

Hom.:

Cov.:

AF XY:

0.0000846

AC XY:

AN XY:

35467

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000920

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000562

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.000106

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

0.65

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.034

Sift

Benign

0.19

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.18

B;.

Vest4

0.24

MutPred

0.13

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);

MVP

0.39

MPC

1.3

ClinPred

0.049

GERP RS

4.1

Varity_R

0.15

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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