X-137567449-G-C

Position:

• chrX-137567449-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PP3_Strong PP5

The ENST00000287538.10(ZIC3):​c.758G>C​(p.Cys253Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ZIC3 ENST00000287538.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript ENST00000287538.10 (ZIC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 545553
• PM1: In a zinc_finger_region C2H2-type 1; atypical (size 35) in uniprot entity ZIC3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000287538.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant X-137567449-G-C is Pathogenic according to our data. Variant chrX-137567449-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 11437.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIC3	NM_003413.4	c.758G>C	p.Cys253Ser	missense_variant	1/3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1	c.758G>C	p.Cys253Ser	missense_variant	1/3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIC3	ENST00000287538.10	c.758G>C	p.Cys253Ser	missense_variant	1/3	1	NM_003413.4	ENSP00000287538	P1
ZIC3	ENST00000370606.3	c.758G>C	p.Cys253Ser	missense_variant	1/3	5		ENSP00000359638

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Heterotaxy, visceral, 1, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.7	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;.
Vest4		0.90
MutPred		0.81		Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);
MVP		0.93
MPC		2.7
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs104894961; hg19: chrX-136649608;