Genetic Variant ZIC3:p.Arg304Arg (chrX-137567603-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003413.4(ZIC3):c.912G>A(p.Arg304Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,211,357 control chromosomes in the GnomAD database, including 4 homozygotes. There are 191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., 82 hem., cov: 25)

Exomes 𝑓: 0.00034 ( 2 hom. 109 hem. )

Consequence

ZIC3
NM_003413.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.461

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant X-137567603-G-A is Benign according to our data. Variant chrX-137567603-G-A is described in ClinVar as Benign. ClinVar VariationId is 239539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.461 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

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.912G>A	p.Arg304Arg	synonymous	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.912G>A	p.Arg304Arg	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.912G>A	p.Arg304Arg	synonymous	Exon 1 of 3	ENSP00000287538.5	O60481-1
ZIC3	ENST00000919832.1		c.912G>A	p.Arg304Arg	synonymous	Exon 4 of 6	ENSP00000589891.1
ZIC3	ENST00000919833.1		c.912G>A	p.Arg304Arg	synonymous	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

327

AN:

113066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000923

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000650

GnomAD2 exomes

AF:

0.00106

AC:

194

AN:

183282

AF XY:

0.000737

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.000693

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000341

AC:

375

AN:

1098241

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

109

AN XY:

363603

show subpopulations

African (AFR)

AF:

0.0121

AC:

319

AN:

26403

American (AMR)

AF:

0.000596

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40509

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

842147

Other (OTH)

AF:

0.000412

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00289

AC:

327

AN:

113116

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

AN XY:

35268

show subpopulations

African (AFR)

AF:

0.0101

AC:

315

AN:

31232

American (AMR)

AF:

0.000922

AC:

AN:

10850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2785

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6268

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53335

Other (OTH)

AF:

0.000642

AC:

AN:

1557

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.00158

Hom.:

Bravo

AF:

0.00403

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.0

(source)

DANN

Benign

0.91

PhyloP100

0.46

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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