NM_003413.4:c.105G>A

Variant names:

• chrX-137566796-G-A
• rs1931349869
• NM_003413.4:c.105G>A

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.105G>A​(p.Met35Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000272 in 1,176,305 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M35V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 25)
  • Exomes 𝑓: 0.000029 (0 hom. 14 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62
• 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=0.100815475).
• BS2: High Hemizygotes in GnomAdExome4 at 14 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.105G>A	p.Met35Ile	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.105G>A	p.Met35Ile	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.105G>A	p.Met35Ile	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.105G>A	p.Met35Ile	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.105G>A	p.Met35Ile	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.00000884 AC: 1 AN: 113101 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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 31 AN: 1063204 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 14 AN XY: 345270

African (AFR) AF: 0.00 AC: 0 AN: 25771

American (AMR) AF: 0.00 AC: 0 AN: 30297

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18782

East Asian (EAS) AF: 0.00 AC: 0 AN: 28576

South Asian (SAS) AF: 0.00 AC: 0 AN: 50737

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3974

European-Non Finnish (NFE) AF: 0.0000339 AC: 28 AN: 826816

Other (OTH) AF: 0.0000669 AC: 3 AN: 44849

GnomAD4 genome AF: 0.00000884 AC: 1 AN: 113101 Hom.: 0 Cov.: 25 AF XY: 0.0000284 AC XY: 1 AN XY: 35247

African (AFR) AF: 0.00 AC: 0 AN: 31206

American (AMR) AF: 0.00 AC: 0 AN: 10834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53322

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

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	Benign	0.30
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.086
Sift	Uncertain	0.019	D
Sift4G	Benign	0.23	T
Polyphen		0.051	B
Vest4		0.13
MutPred		0.23		Gain of loop (P = 0.0435)
MVP		0.068
MPC		1.4
ClinPred		0.31	T
GERP RS		0.94
PromoterAI		0.0060	Neutral
Varity_R		0.31
gMVP		0.34
Mutation Taster		=97/3	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: rs1931349869; hg19: chrX-136648955;