X-137566807-C-T

Variant names:

• chrX-137566807-C-T
• rs1302645424
• NM_003413.4:c.116C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003413.4(ZIC3):​c.116C>T​(p.Pro39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000512 in 1,171,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 0.0000038 (0 hom. 0 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.25
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24439424).

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.116C>T	p.Pro39Leu	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.116C>T	p.Pro39Leu	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.116C>T	p.Pro39Leu	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.116C>T	p.Pro39Leu	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.116C>T	p.Pro39Leu	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112965 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000378 AC: 4 AN: 1058434 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 343752

African (AFR) AF: 0.00 AC: 0 AN: 25579

American (AMR) AF: 0.00 AC: 0 AN: 29493

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18723

East Asian (EAS) AF: 0.00 AC: 0 AN: 28196

South Asian (SAS) AF: 0.00 AC: 0 AN: 50479

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32711

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3983

European-Non Finnish (NFE) AF: 0.00000485 AC: 4 AN: 824578

Other (OTH) AF: 0.00 AC: 0 AN: 44692

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112965 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35109

African (AFR) AF: 0.00 AC: 0 AN: 31202

American (AMR) AF: 0.00 AC: 0 AN: 10839

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6191

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53283

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Heterotaxy, visceral, 1, X-linked (1)
-	1	-	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.49	P
Vest4		0.46
MutPred		0.33		Loss of glycosylation at T44 (P = 0.0643)
MVP		0.20
MPC		2.5
ClinPred		0.99	D
GERP RS		3.3
PromoterAI		0.034	Neutral
Varity_R		0.57
gMVP		0.66
Mutation Taster		=72/28	polymorphism

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: rs1302645424; hg19: chrX-136648966; COSMIC: COSV105154806; COSMIC: COSV105154806;