13-99970388-G-A

Variant names:

• chr13-99970388-G-A
• rs745913274
• NM_033132.5:c.1216C>T

Variant summary

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

The NM_033132.5(ZIC5):​c.1216C>T​(p.Pro406Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,370,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ZIC5 NM_033132.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349
• Publications: 0 publications found

Genes affected

ZIC5 (HGNC:20322): (Zic family member 5) This gene encodes a member of the ZIC family of C2H2-type zinc finger proteins. The encoded protein may act as a transcriptional repressor. Studies in mouse and Xenopus support a role for this gene in neural crest development. Elevated expression of this gene has been observed in various human cancers and may contribute to cancer progression. This gene is closely linked to a related family member on chromosome 13. [provided by RefSeq, Mar 2017]

ENSG00000297638 (HGNC:):

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=0.040779382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5	c.1216C>T	p.Pro406Ser	missense_variant	Exon 1 of 2	ENST00000267294.5	NP_149123.3
ZIC5	NR_146224.1	n.1522C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZIC5	ENST00000267294.5	c.1216C>T	p.Pro406Ser	missense_variant	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4
ENSG00000297638	ENST00000749511.1	n.135+260G>A		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1	n.104+254G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000214 AC: 3 AN: 140426 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000696

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: 0.000526

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1230156 Hom.: 0 Cov.: 30 AF XY: 0.00000166 AC XY: 1 AN XY: 601032

African (AFR) AF: 0.00 AC: 0 AN: 27130

American (AMR) AF: 0.00 AC: 0 AN: 30442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20696

East Asian (EAS) AF: 0.00 AC: 0 AN: 30104

South Asian (SAS) AF: 0.00 AC: 0 AN: 43840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4910

European-Non Finnish (NFE) AF: 0.00000203 AC: 2 AN: 987652

Other (OTH) AF: 0.00 AC: 0 AN: 49068

GnomAD4 genome AF: 0.0000214 AC: 3 AN: 140426 Hom.: 0 Cov.: 29 AF XY: 0.0000146 AC XY: 1 AN XY: 68622

African (AFR) AF: 0.0000269 AC: 1 AN: 37112

American (AMR) AF: 0.0000696 AC: 1 AN: 14368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4660

South Asian (SAS) AF: 0.00 AC: 0 AN: 4366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64742

Other (OTH) AF: 0.000526 AC: 1 AN: 1900

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1288C>T (p.P430S) alteration is located in exon 1 (coding exon 1) of the ZIC5 gene. This alteration results from a C to T substitution at nucleotide position 1288, causing the proline (P) at amino acid position 430 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.67	N
PhyloP100		0.35
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.020
Sift	Benign	0.80	T
Sift4G	Benign	1.0	T
Polyphen		0.42	B
Vest4		0.067
MutPred		0.28		Gain of catalytic residue at K433 (P = 0);
MVP		0.24
ClinPred		0.10	T
GERP RS		2.0
Varity_R		0.069
gMVP		0.73
Mutation Taster		=89/11	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: rs745913274; hg19: chr13-100622642; COSMIC: COSV99940731;