Genetic Variant ZIC3:p.Pro12Pro (chrX-137566727-T-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_003413.4(ZIC3):c.36T>C(p.Pro12Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,196,021 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 25)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

ZIC3
NM_003413.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.356

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]

ZIC3 links:

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

LINC02931 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant X-137566727-T-C is Benign according to our data. Variant chrX-137566727-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2183993.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.356 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	NM_003413.4	MANE Select	c.36T>C	p.Pro12Pro	synonymous	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.36T>C	p.Pro12Pro	synonymous	Exon 1 of 3	NP_001317590.1	O60481-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.36T>C	p.Pro12Pro	synonymous	Exon 1 of 3	ENSP00000287538.5	O60481-1
ZIC3	ENST00000919832.1		c.36T>C	p.Pro12Pro	synonymous	Exon 4 of 6	ENSP00000589891.1
ZIC3	ENST00000919833.1		c.36T>C	p.Pro12Pro	synonymous	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes

AF:

0.00000884

AC:

AN:

113069

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000922

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

GnomAD2 exomes

AF:

0.00000669

AC:

AN:

149567

AF XY:

0.0000217

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000399

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

9.23e-7

AC:

AN:

1082952

Hom.:

Cov.:

AF XY:

0.00000283

AC XY:

AN XY:

352762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26214

American (AMR)

AF:

0.0000296

AC:

AN:

33762

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19089

East Asian (EAS)

AF:

0.00

AC:

AN:

29667

South Asian (SAS)

AF:

0.00

AC:

AN:

51925

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4001

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835570

Other (OTH)

AF:

0.00

AC:

AN:

45510

Age Distribution

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:

0.00000884

AC:

AN:

113069

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35209

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31187

American (AMR)

AF:

0.0000922

AC:

AN:

10849

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2799

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53304

Other (OTH)

AF:

0.00

AC:

AN:

1519

Age Distribution

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:

0.0000113

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Heterotaxy, visceral, 1, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.9

(source)

DANN

Benign

0.69

PhyloP100

-0.36

PromoterAI

0.0098

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over