chrX-137566788-G-T

Variant names:

• chrX-137566788-G-T
• rs746833203
• NM_003413.4:c.97G>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.97G>T​(p.Ala33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,178,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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. A33V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 8 hem., cov: 25)
  • Exomes 𝑓: 0.000011 (0 hom. 3 hem.)
• Consequence: ZIC3 NM_003413.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.766
• 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=0.07871276).
• BS2: High Hemizygotes in GnomAd4 at 8 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.97G>T	p.Ala33Ser	missense	Exon 1 of 3	NP_003404.1	O60481-1
	ZIC3	NM_001330661.1		c.97G>T	p.Ala33Ser	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.97G>T	p.Ala33Ser	missense	Exon 1 of 3	ENSP00000287538.5	O60481-1
	ZIC3	ENST00000919832.1		c.97G>T	p.Ala33Ser	missense	Exon 4 of 6	ENSP00000589891.1
	ZIC3	ENST00000919833.1		c.97G>T	p.Ala33Ser	missense	Exon 4 of 6	ENSP00000589892.1

Frequencies

GnomAD3 genomes AF: 0.000186 AC: 21 AN: 113197 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000921

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 2 AN: 123398 AF XY: 0.0000258

Gnomad AFR exome AF: 0.000254

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: 0.0000113 AC: 12 AN: 1065512 Hom.: 0 Cov.: 32 AF XY: 0.00000867 AC XY: 3 AN XY: 345840

African (AFR) AF: 0.000232 AC: 6 AN: 25864

American (AMR) AF: 0.00 AC: 0 AN: 30748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18817

East Asian (EAS) AF: 0.00 AC: 0 AN: 28755

South Asian (SAS) AF: 0.00 AC: 0 AN: 50884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33733

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3954

European-Non Finnish (NFE) AF: 0.00000242 AC: 2 AN: 827826

Other (OTH) AF: 0.0000890 AC: 4 AN: 44931

GnomAD4 genome AF: 0.000186 AC: 21 AN: 113197 Hom.: 0 Cov.: 25 AF XY: 0.000226 AC XY: 8 AN XY: 35337

African (AFR) AF: 0.000640 AC: 20 AN: 31258

American (AMR) AF: 0.0000921 AC: 1 AN: 10857

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6267

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53333

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.0000176 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.77
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.042
Sift	Benign	0.21	T
Sift4G	Benign	0.64	T
Polyphen		0.67	P
Vest4		0.20
MVP		0.23
MPC		1.2
ClinPred		0.052	T
GERP RS		3.2
PromoterAI		-0.034	Neutral
Varity_R		0.12
gMVP		0.10
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: rs746833203; hg19: chrX-136648947; COSMIC: COSV54977378; COSMIC: COSV54977378;