chr13-99970359-G-C

Variant names:

• chr13-99970359-G-C
• rs751843721
• NM_033132.5:c.1245C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_033132.5(ZIC5):​c.1245C>G​(p.His415Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,603,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ZIC5 NM_033132.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32762277).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZIC5	NM_033132.5	c.1245C>G	p.His415Gln	missense_variant	Exon 1 of 2	ENST00000267294.5	NP_149123.3
ZIC5	NR_146224.1	n.1551C>G		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.1245C>G	p.His415Gln	missense_variant	Exon 1 of 2	1	NM_033132.5	ENSP00000267294.4
ENSG00000297638	ENST00000749511.1	n.135+231G>C		intron_variant	Intron 1 of 1
ENSG00000297638	ENST00000749512.1	n.104+225G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000338 AC: 5 AN: 147970 Hom.: 0 Cov.: 30

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: 0.000400

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 6 AN: 246664 AF XY: 0.0000299

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: 0.000247

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1455386 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 724014

African (AFR) AF: 0.00 AC: 0 AN: 33180

American (AMR) AF: 0.00 AC: 0 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39276

South Asian (SAS) AF: 0.00 AC: 0 AN: 85970

European-Finnish (FIN) AF: 0.000466 AC: 24 AN: 51544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109252

Other (OTH) AF: 0.0000333 AC: 2 AN: 60090

GnomAD4 genome AF: 0.0000338 AC: 5 AN: 147970 Hom.: 0 Cov.: 30 AF XY: 0.0000415 AC XY: 3 AN XY: 72212

African (AFR) AF: 0.00 AC: 0 AN: 39972

American (AMR) AF: 0.00 AC: 0 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4844

South Asian (SAS) AF: 0.00 AC: 0 AN: 4606

European-Finnish (FIN) AF: 0.000400 AC: 4 AN: 10004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66936

Other (OTH) AF: 0.00 AC: 0 AN: 2018

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1317C>G (p.H439Q) alteration is located in exon 1 (coding exon 1) of the ZIC5 gene. This alteration results from a C to G substitution at nucleotide position 1317, causing the histidine (H) at amino acid position 439 to be replaced by a glutamine (Q). 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	Pathogenic	0.89
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.27
MutPred		0.35		Gain of catalytic residue at H444 (P = 0.0201);
MVP		0.43
ClinPred		0.46	T
GERP RS		4.4
Varity_R		0.62
gMVP		0.55
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751843721; hg19: chr13-100622613; COSMIC: COSV57436986;