rs780929975

Variant names:

• chrX-137566794-A-G
• rs780929975
• NM_003413.4:c.103A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003413.4(ZIC3):​c.103A>G​(p.Met35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,063,059 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. M35I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.518
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040149897).

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.103A>G	p.Met35Val	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.103A>G	p.Met35Val	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.103A>G	p.Met35Val	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.103A>G	p.Met35Val	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.103A>G	p.Met35Val	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000250 AC: 3 AN: 119766 AF XY: 0.0000261

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000940

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000206

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 3 AN: 1063059 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 1 AN XY: 345067

African (AFR) AF: 0.00 AC: 0 AN: 25772

American (AMR) AF: 0.0000661 AC: 2 AN: 30270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18787

East Asian (EAS) AF: 0.00 AC: 0 AN: 28579

South Asian (SAS) AF: 0.00 AC: 0 AN: 50725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3967

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826700

Other (OTH) AF: 0.00 AC: 0 AN: 44843

GnomAD4 genome Cov.: 25

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000899 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ZIC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.52
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.019
Sift	Benign	0.091	T
Sift4G	Benign	0.62	T
Polyphen		0.022	B
Vest4		0.098
MutPred		0.22		Loss of loop (P = 0.0203)
MVP		0.082
MPC		1.3
ClinPred		0.025	T
GERP RS		3.0
PromoterAI		-0.012	Neutral
Varity_R		0.20
gMVP		0.41
Mutation Taster		=99/1	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: rs780929975; hg19: chrX-136648953;