X-137566722-T-C

Variant names:

• chrX-137566722-T-C
• rs1327091342
• NM_003413.4:c.31T>C

Variant summary

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

The NM_003413.4(ZIC3):​c.31T>C​(p.Phe11Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,083,739 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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=0.20461532).
• 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	c.31T>C	p.Phe11Leu	missense_variant	Exon 1 of 3	ENST00000287538.10	NP_003404.1
ZIC3	NM_001330661.1	c.31T>C	p.Phe11Leu	missense_variant	Exon 1 of 3		NP_001317590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC3	ENST00000287538.10	c.31T>C	p.Phe11Leu	missense_variant	Exon 1 of 3	1	NM_003413.4	ENSP00000287538.5
ZIC3	ENST00000370606.3	c.31T>C	p.Phe11Leu	missense_variant	Exon 1 of 3	5		ENSP00000359638.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000664 AC: 1 AN: 150506 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 46512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000620

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1083739 Hom.: 0 Cov.: 32 AF XY: 0.00000566 AC XY: 2 AN XY: 353207

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: 0.0000577

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 13, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.12
Sift	Benign	0.038	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.33	B;.
Vest4		0.41
MutPred		0.26		Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);
MVP		0.21
MPC		2.5
ClinPred		0.42	T
GERP RS		4.0
Varity_R		0.43
gMVP		0.44

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: rs1327091342; hg19: chrX-136648881;