rs104894963

Variant names:

• chrX-137567340-C-G
• rs104894963
• NM_003413.4:c.649C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-137567340-C-G
• chrX-137567340-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003413.4(ZIC3):​c.649C>G​(p.Pro217Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00106 in 1,210,097 control chromosomes in the GnomAD database, including 14 homozygotes. There are 310 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., 168 hem., cov: 25)
  • Exomes 𝑓: 0.00056 (5 hom. 142 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 5.97
• Publications: 7 publications found

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]

LINC02931 (HGNC:55853): (long intergenic non-protein coding RNA 2931)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005806178).
• BP6: Variant X-137567340-C-G is Benign according to our data. Variant chrX-137567340-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 11439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.006 (675/112410) while in subpopulation AFR AF = 0.0208 (646/31003). AF 95% confidence interval is 0.0195. There are 9 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	NM_003413.4	MANE Select	c.649C>G	p.Pro217Ala	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.649C>G	p.Pro217Ala	missense	Exon 1 of 3	NP_001317590.1	O60481-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.649C>G	p.Pro217Ala	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.649C>G	p.Pro217Ala	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.649C>G	p.Pro217Ala	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 674 AN: 112356 Hom.: 9 Cov.: 25

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00151 AC: 272 AN: 180381 AF XY: 0.000838

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000558 AC: 612 AN: 1097687 Hom.: 5 Cov.: 33 AF XY: 0.000391 AC XY: 142 AN XY: 363377

African (AFR) AF: 0.0192 AC: 508 AN: 26403

American (AMR) AF: 0.00108 AC: 38 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39969

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842142

Other (OTH) AF: 0.00132 AC: 61 AN: 46092

GnomAD4 genome AF: 0.00600 AC: 675 AN: 112410 Hom.: 9 Cov.: 25 AF XY: 0.00486 AC XY: 168 AN XY: 34580

African (AFR) AF: 0.0208 AC: 646 AN: 31003

American (AMR) AF: 0.00223 AC: 24 AN: 10754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3522

South Asian (SAS) AF: 0.00 AC: 0 AN: 2721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6157

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53180

Other (OTH) AF: 0.00196 AC: 3 AN: 1530

Alfa AF: 0.00107 Hom.: 24

Bravo AF: 0.00680

ESP6500AA AF: 0.0205 AC: 78

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00156 AC: 189

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Heterotaxy, visceral, 1, X-linked (2)
-	-	1	Congenital heart defects 1, nonsyndromic, 1 (1)
-	1	-	Congenital heart defects, multiple types, 1, X-linked (1)
-	-	1	not specified (1)
-	-	1	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.10
Sift	Uncertain	0.014	D
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.18
MPC		1.2
ClinPred		0.044	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.30
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs104894963; hg19: chrX-136649499; COSMIC: COSV54974078;