rs62637689

Positions:

• chrX-137566853-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003413.4(ZIC3):​c.162T>C​(p.Ala54=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,160,326 control chromosomes in the GnomAD database, including 15 homozygotes. There are 634 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (7 hom., 313 hem., cov: 25)
  • Exomes 𝑓: 0.0012 (8 hom. 321 hem.)
• Consequence: ZIC3 NM_003413.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.87

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-137566853-T-C is Benign according to our data. Variant chrX-137566853-T-C is described in ClinVar as [Benign]. Clinvar id is 137958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-137566853-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00919 (1037/112782) while in subpopulation AFR AF= 0.0302 (942/31201). AF 95% confidence interval is 0.0286. There are 7 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZIC3	NM_003413.4	c.162T>C	p.Ala54=	synonymous_variant	1/3	ENST00000287538.10
ZIC3	NM_001330661.1	c.162T>C	p.Ala54=	synonymous_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZIC3	ENST00000287538.10	c.162T>C	p.Ala54=	synonymous_variant	1/3	1	NM_003413.4	P1
ZIC3	ENST00000370606.3	c.162T>C	p.Ala54=	synonymous_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00917 AC: 1034 AN: 112728 Hom.: 7 Cov.: 25 AF XY: 0.00889 AC XY: 311 AN XY: 34990

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000848

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000394

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00229 AC: 235 AN: 102752 Hom.: 5 AF XY: 0.00152 AC XY: 55 AN XY: 36206

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00226

GnomAD4 exome AF: 0.00116 AC: 1211 AN: 1047544 Hom.: 8 Cov.: 33 AF XY: 0.000940 AC XY: 321 AN XY: 341514

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000515

Gnomad4 SAS exome AF: 0.0000402

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000268

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00919 AC: 1037 AN: 112782 Hom.: 7 Cov.: 25 AF XY: 0.00893 AC XY: 313 AN XY: 35054

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.00479

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000851

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000394

Gnomad4 OTH AF: 0.0122

Alfa AF: 0.00465 Hom.: 26

Bravo AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.60

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: rs62637689; hg19: chrX-136649012;