rs387906498

chrX-137569063-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_003413.4(ZIC3):c.1222A>T(p.Lys408Ter) variant causes a stop gained, splice region 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).

• Frequency: Genomes: not found (cov: 20)
• Consequence: ZIC3 NM_003413.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9683
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.13 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-137569063-A-T is Pathogenic according to our data. Variant chrX-137569063-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11435.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.1222A>T	p.Lys408Ter	stop_gained, splice_region_variant	2/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.1222A>T	p.Lys408Ter	stop_gained, splice_region_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.1222A>T	p.Lys408Ter	stop_gained, splice_region_variant	2/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.1222A>T	p.Lys408Ter	stop_gained, splice_region_variant	2/3	5
ZIC3	ENST00000478471.1	n.259A>T		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital heart defects, multiple types, 1, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	52
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D
Vest4		0.79
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: -2
DS_DL_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906498; hg19: chrX-136651222;