Genetic Variant NM_003413.4:c.49G>T (chrX-137566740-G-T) – ACMG Classification: Benign (-16 pts)

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.49G>T(p.Gly17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,190,354 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,091 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 0.0020 ( 0 hom., 65 hem., cov: 24)

Exomes 𝑓: 0.0031 ( 7 hom. 1026 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:13

Conservation

PhyloP100: 1.85

Publications

10 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=0.0077534616).

BP6

Variant X-137566740-G-T is Benign according to our data. Variant chrX-137566740-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 65 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.49G>T	p.Gly17Cys	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.49G>T	p.Gly17Cys	missense	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.49G>T	p.Gly17Cys	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
ZIC3	ENST00000919832.1		c.49G>T	p.Gly17Cys	missense	Exon 4 of 6	ENSP00000589891.1
ZIC3	ENST00000919833.1		c.49G>T	p.Gly17Cys	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

227

AN:

113102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000320

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.000830

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00463

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00328

GnomAD2 exomes

AF:

0.00259

AC:

366

AN:

141061

AF XY:

0.00239

show subpopulations

Gnomad AFR exome

AF:

0.000408

Gnomad AMR exome

AF:

0.000998

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00532

Gnomad NFE exome

AF:

0.00436

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.00311

AC:

3350

AN:

1077197

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

1026

AN XY:

349763

show subpopulations

African (AFR)

AF:

0.000421

AC:

AN:

26120

American (AMR)

AF:

0.000943

AC:

AN:

32871

Ashkenazi Jewish (ASJ)

AF:

0.00147

AC:

AN:

18998

East Asian (EAS)

AF:

0.00

AC:

AN:

29353

South Asian (SAS)

AF:

0.0000777

AC:

AN:

51477

European-Finnish (FIN)

AF:

0.00515

AC:

187

AN:

36317

Middle Eastern (MID)

AF:

0.000252

AC:

AN:

3966

European-Non Finnish (NFE)

AF:

0.00353

AC:

2937

AN:

832809

Other (OTH)

AF:

0.00333

AC:

151

AN:

45286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

168

336

505

673

841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00201

AC:

227

AN:

113157

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

AN XY:

35315

show subpopulations

African (AFR)

AF:

0.000320

AC:

AN:

31274

American (AMR)

AF:

0.000829

AC:

AN:

10853

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2792

European-Finnish (FIN)

AF:

0.00463

AC:

AN:

6267

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00315

AC:

168

AN:

53332

Other (OTH)

AF:

0.00324

AC:

AN:

1545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.00308

Hom.:

Bravo

AF:

0.00164

ESP6500AA

AF:

0.00131

AC:

ESP6500EA

AF:

0.00388

AC:

ExAC

AF:

0.00268

AC:

318

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Heterotaxy, visceral, 1, X-linked (4)

not specified (2)

VACTERL association, X-linked, with or without hydrocephalus (2)

Congenital heart defects 1, nonsyndromic, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0078

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.1

PhyloP100

1.9

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.29

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.48

MVP

0.65

MPC

2.4

ClinPred

0.018

GERP RS

3.3

PromoterAI

-0.032

Neutral

(source)

Varity_R

0.51

gMVP

0.64

Mutation Taster

=39/61

disease causing (ClinVar)

(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