X-137566789-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A33S) has been classified as Uncertain significance.

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

Publications

2 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]

ZIC3 links:

LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

LINC02931 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ZIC3	NM_003413.4 link	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1 link	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 3		NP_001317590.1	O60481-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZIC3	ENST00000287538.10 link	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5	O60481-1
ZIC3	ENST00000370606.3 link	c.98C>T	p.Ala33Val	missense_variant	Exon 1 of 3	5		ENSP00000359638.3	O60481-2
LINC02931	ENST00000786828.1 link	n.130+2285G>A		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000441

AC:

AN:

113273

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000113

AC:

AN:

123646

AF XY:

0.000103

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 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

African (AFR)

AF:

0.00

AC:

AN:

25867

American (AMR)

AF:

0.0000325

AC:

AN:

30756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18821

East Asian (EAS)

AF:

0.000765

AC:

AN:

28752

South Asian (SAS)

AF:

0.000118

AC:

AN:

50887

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33837

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3959

European-Non Finnish (NFE)

AF:

0.0000447

AC:

AN:

827948

Other (OTH)

AF:

0.0000668

AC:

AN:

44932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000441

AC:

AN:

113327

Hom.:

Cov.:

AF XY:

0.0000846

AC XY:

AN XY:

35467

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31357

American (AMR)

AF:

0.0000920

AC:

AN:

10868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.000281

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6291

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000562

AC:

AN:

53337

Other (OTH)

AF:

0.00

AC:

AN:

1553

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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.:

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

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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

PhyloP100

2.4

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

PromoterAI

0.025

Neutral

(source)

Varity_R

0.15

gMVP

0.24

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over