7-130023534-G-A

Position:

• chr7-130023534-G-A

Variant summary

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

The NM_016478.5(ZC3HC1):​c.1210C>T​(p.Arg404Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZC3HC1 NM_016478.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05

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.1210C>T	p.Arg404Cys	missense_variant	8/10	ENST00000358303.9	NP_057562.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3HC1	ENST00000358303.9	c.1210C>T	p.Arg404Cys	missense_variant	8/10	1	NM_016478.5	ENSP00000351052.4
ZC3HC1	ENST00000481503.5	c.1081C>T	p.Arg361Cys	missense_variant	8/10	5		ENSP00000418533.1
ZC3HC1	ENST00000467642.5	n.*1094C>T		non_coding_transcript_exon_variant	9/11	2		ENSP00000419509.1
ZC3HC1	ENST00000648450.1	n.*1220C>T		non_coding_transcript_exon_variant	10/12			ENSP00000498166.1
ZC3HC1	ENST00000467642.5	n.*1094C>T		3_prime_UTR_variant	9/11	2		ENSP00000419509.1
ZC3HC1	ENST00000648450.1	n.*1220C>T		3_prime_UTR_variant	10/12			ENSP00000498166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

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

Dec 06, 2023

The c.1210C>T (p.R404C) alteration is located in exon 8 (coding exon 8) of the ZC3HC1 gene. This alteration results from a C to T substitution at nucleotide position 1210, causing the arginine (R) at amino acid position 404 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.48	P;.;P
Vest4		0.66
MutPred		0.40		Loss of MoRF binding (P = 0.0071);.;.;
MVP		0.60
MPC		1.0
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.36
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1563073957; hg19: chr7-129663374; COSMIC: COSV61300244; COSMIC: COSV61300244;