dbSNP rs143990850: ZIC3:p.Thr398Thr (chrX-137569035-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_003413.4(ZIC3):c.1194G>T(p.Thr398Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,209,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.000028 ( 0 hom. 13 hem. )

Consequence

ZIC3
NM_003413.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0650

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant X-137569035-G-T is Benign according to our data. Variant chrX-137569035-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195195.

BP7

Synonymous conserved (PhyloP=0.065 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4 link	c.1194G>T	p.Thr398Thr	synonymous_variant	Exon 2 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1 link	c.1194G>T	p.Thr398Thr	synonymous_variant	Exon 2 of 3		NP_001317590.1	O60481-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZIC3	ENST00000287538.10 link	c.1194G>T	p.Thr398Thr	synonymous_variant	Exon 2 of 3	1	NM_003413.4	ENSP00000287538.5	O60481-1
ZIC3	ENST00000370606.3 link	c.1194G>T	p.Thr398Thr	synonymous_variant	Exon 2 of 3	5		ENSP00000359638.3	O60481-2
ZIC3	ENST00000478471.1 link	n.231G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
LINC02931	ENST00000786828.1 link	n.130+39C>A		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.000153

AC:

AN:

110957

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000558

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

GnomAD2 exomes

AF:

0.000104

AC:

AN:

183441

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000282

AC:

AN:

1098182

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363538

show subpopulations

African (AFR)

AF:

0.000909

AC:

AN:

26398

American (AMR)

AF:

0.000114

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

842092

Other (OTH)

AF:

0.0000217

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000153

AC:

AN:

111002

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

33210

show subpopulations

African (AFR)

AF:

0.000557

AC:

AN:

30509

American (AMR)

AF:

0.00

AC:

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3477

South Asian (SAS)

AF:

0.00

AC:

AN:

2582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5879

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52959

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000174

Hom.:

Bravo

AF:

0.000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 31, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Heterotaxy, visceral, 1, X-linked

Benign:1

Dec 19, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.8

(source)

DANN

Benign

0.85

PhyloP100

0.065

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over