X-137566783-A-T

Position:

• chrX-137566783-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003413.4(ZIC3):​c.92A>T​(p.Glu31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,068,827 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000056 (0 hom. 3 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18874282).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.92A>T	p.Glu31Val	missense_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.92A>T	p.Glu31Val	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.92A>T	p.Glu31Val	missense_variant	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.92A>T	p.Glu31Val	missense_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000561 AC: 6 AN: 1068827 Hom.: 0 Cov.: 32 AF XY: 0.00000865 AC XY: 3 AN XY: 346935

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000723

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000174 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2019

This sequence change replaces glutamic acid with valine at codon 31 of the ZIC3 protein (p.Glu31Val). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and valine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ZIC3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.090
Sift	Benign	0.068	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.97	D;.
Vest4		0.29
MutPred		0.25		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP		0.42
MPC		1.5
ClinPred		0.56	D
GERP RS		4.1
Varity_R		0.33
gMVP		0.52

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: rs752686913; hg19: chrX-136648942;