rs886041111

Variant names:

• chrX-137567455-G-C
• rs886041111
• NM_003413.4:c.764G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_003413.4(ZIC3):​c.764G>C​(p.Trp255Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W255G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99
• Publications: 0 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_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-137567454-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11441.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant X-137567455-G-C is Pathogenic according to our data. Variant chrX-137567455-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 279591.Status of the report is criteria_provided_single_submitter, 1 stars.

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.764G>C	p.Trp255Ser	missense	Exon 1 of 3	NP_003404.1
	ZIC3	NM_001330661.1		c.764G>C	p.Trp255Ser	missense	Exon 1 of 3	NP_001317590.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZIC3	ENST00000287538.10	TSL:1 MANE Select	c.764G>C	p.Trp255Ser	missense	Exon 1 of 3	ENSP00000287538.5
	ZIC3	ENST00000919832.1		c.764G>C	p.Trp255Ser	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.764G>C	p.Trp255Ser	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Heterotaxy, visceral, 1, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-14	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.66		Gain of disorder (P = 0)
MVP		0.97
MPC		3.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.93
Mutation Taster		=1/99	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: rs886041111; hg19: chrX-136649614;