Genetic Variant ZIC3:p.Pro217Ser (chrX-137567340-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003413.4(ZIC3):c.649C>T(p.Pro217Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,687 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P217A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000018 ( 0 hom. 2 hem. )

Consequence

ZIC3
NM_003413.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.97

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16606942).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC3	NM_003413.4 link	c.649C>T	p.Pro217Ser	missense_variant	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1 link	c.649C>T	p.Pro217Ser	missense_variant	Exon 1 of 3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ZIC3	ENST00000287538.10 link	c.649C>T	p.Pro217Ser	missense_variant	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5
ZIC3	ENST00000370606.3 link	c.649C>T	p.Pro217Ser	missense_variant	Exon 1 of 3	5		ENSP00000359638.3
LINC02931	ENST00000786828.1 link	n.130+1734G>A		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097687

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363377

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39969

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842142

Other (OTH)

AF:

0.00

AC:

AN:

46092

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PhyloP100

6.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.66

N;N

REVEL

Benign

0.093

Sift

Benign

0.037

D;D

Sift4G

Benign

0.40

T;T

Polyphen

0.0

B;.

Vest4

0.16

MutPred

0.32

Gain of glycosylation at P217 (P = 0.1228);Gain of glycosylation at P217 (P = 0.1228);

MVP

0.21

MPC

1.3

ClinPred

0.85

GERP RS

3.7

Varity_R

0.094

gMVP

0.34

Mutation Taster

=92/8

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over