NM_003413.4:c.92A>T

Variant names:

• chrX-137566783-A-T
• rs752686913
• NM_003413.4:c.92A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003413.4(ZIC3):​c.92A>T​(p.Glu31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,068,827 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000056 (0 hom. 3 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18874282).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.92A>T	p.Glu31Val	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.92A>T	p.Glu31Val	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.92A>T	p.Glu31Val	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.92A>T	p.Glu31Val	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.92A>T	p.Glu31Val	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 127773 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000561 AC: 6 AN: 1068827 Hom.: 0 Cov.: 32 AF XY: 0.00000865 AC XY: 3 AN XY: 346935

African (AFR) AF: 0.00 AC: 0 AN: 25972

American (AMR) AF: 0.00 AC: 0 AN: 31304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18865

East Asian (EAS) AF: 0.00 AC: 0 AN: 28953

South Asian (SAS) AF: 0.00 AC: 0 AN: 51109

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3969

European-Non Finnish (NFE) AF: 0.00000723 AC: 6 AN: 829316

Other (OTH) AF: 0.00 AC: 0 AN: 45039

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000174 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	Uncertain	0.40
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.090
Sift	Benign	0.068	T
Sift4G	Benign	0.23	T
Polyphen		0.97	D
Vest4		0.29
MutPred		0.25		Loss of loop (P = 0.0073)
MVP		0.42
MPC		1.5
ClinPred		0.56	D
GERP RS		4.1
PromoterAI		-0.073	Neutral
Varity_R		0.33
gMVP		0.52
Mutation Taster		=66/34	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: rs752686913; hg19: chrX-136648942;