chr7-130039482-G-A

Position:

• chr7-130039482-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016478.5(ZC3HC1):​c.475C>T​(p.Pro159Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZC3HC1 NM_016478.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.33

Genes affected

ZC3HC1 (HGNC:29913): (zinc finger C3HC-type containing 1) This gene encodes an F-box-containing protein that is a component of an SCF-type E3 ubiquitin ligase complex that regulates the onset of cell division. The G2/M transition in the cell cycle requires the interaction of the proteins cyclin B1 and cyclin-dependent kinase 1. The activated ubiquitin ligase complex targets the protein cyclin B1 for degradation, preventing this transition to mitosis. [provided by RefSeq, Aug 2013]

ZC3HC1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3HC1	NM_016478.5	c.475C>T	p.Pro159Ser	missense_variant	4/10	ENST00000358303.9	NP_057562.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3HC1	ENST00000358303.9	c.475C>T	p.Pro159Ser	missense_variant	4/10	1	NM_016478.5	ENSP00000351052.4
ZC3HC1	ENST00000481503.5	c.475C>T	p.Pro159Ser	missense_variant	4/10	5		ENSP00000418533.1
ZC3HC1	ENST00000467642.5	n.*359C>T		non_coding_transcript_exon_variant	5/11	2		ENSP00000419509.1
ZC3HC1	ENST00000648450.1	n.*485C>T		non_coding_transcript_exon_variant	6/12			ENSP00000498166.1
ZC3HC1	ENST00000467642.5	n.*359C>T		3_prime_UTR_variant	5/11	2		ENSP00000419509.1
ZC3HC1	ENST00000648450.1	n.*485C>T		3_prime_UTR_variant	6/12			ENSP00000498166.1
ZC3HC1	ENST00000470651.1	n.*428C>T		downstream_gene_variant		4		ENSP00000420068.1
ZC3HC1	ENST00000484432.1	n.*289C>T		downstream_gene_variant		4		ENSP00000417217.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459878 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.475C>T (p.P159S) alteration is located in exon 4 (coding exon 4) of the ZC3HC1 gene. This alteration results from a C to T substitution at nucleotide position 475, causing the proline (P) at amino acid position 159 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.075	T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.55
MutPred		0.70		Gain of relative solvent accessibility (P = 0.005);.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP		0.63
MPC		0.59
ClinPred		0.88	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1419847786; hg19: chr7-129679322;