NM_003413.4:c.19G>C

Variant names:

• chrX-137566710-G-C
• rs763534805
• NM_003413.4:c.19G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_003413.4(ZIC3):​c.19G>C​(p.Gly7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,085,516 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000016 (0 hom. 10 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.29
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant X-137566710-G-C is Pathogenic according to our data. Variant chrX-137566710-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418553.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16089576). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAdExome4 at 10 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.19G>C	p.Gly7Arg	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.19G>C	p.Gly7Arg	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.19G>C	p.Gly7Arg	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.19G>C	p.Gly7Arg	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.19G>C	p.Gly7Arg	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000652 AC: 1 AN: 153469 AF XY: 0.0000209

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 17 AN: 1085516 Hom.: 0 Cov.: 32 AF XY: 0.0000282 AC XY: 10 AN XY: 354398

African (AFR) AF: 0.00 AC: 0 AN: 26222

American (AMR) AF: 0.00 AC: 0 AN: 34134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19151

East Asian (EAS) AF: 0.00 AC: 0 AN: 29743

South Asian (SAS) AF: 0.00 AC: 0 AN: 52190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.0000191 AC: 16 AN: 836916

Other (OTH) AF: 0.0000219 AC: 1 AN: 45625

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Heterotaxy, visceral, 1, X-linked (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.21
MutPred		0.14		Gain of sheet (P = 0.0101)
MVP		0.16
MPC		2.2
ClinPred		0.70	D
GERP RS		3.2
PromoterAI		0.012	Neutral
Varity_R		0.40
gMVP		0.54
Mutation Taster		=55/45	disease causing (ClinVar)

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: rs763534805; hg19: chrX-136648869;