Variant 7-130039466-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016478.5(ZC3HC1):c.491C>A(p.Pro164Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZC3HC1
NM_016478.5 missense, splice_region

Scores

Splicing: ADA: 0.01510

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.33

Variant links:

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 links:

ZC3HC1 (HGNC:):

ZC3HC1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3HC1	NM_016478.5 linkuse as main transcript	c.491C>A	p.Pro164Gln	missense_variant, splice_region_variant	4/10	ENST00000358303.9	NP_057562.3	Q86WB0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZC3HC1	ENST00000358303.9 linkuse as main transcript	c.491C>A	p.Pro164Gln	missense_variant, splice_region_variant	4/10	1	NM_016478.5	ENSP00000351052.4	Q86WB0-1
ZC3HC1	ENST00000481503.5 linkuse as main transcript	c.491C>A	p.Pro164Gln	missense_variant, splice_region_variant	4/10	5		ENSP00000418533.1	C9J0I9
ZC3HC1	ENST00000467642.5 linkuse as main transcript	n.*375C>A		splice_region_variant, non_coding_transcript_exon_variant	5/11	2		ENSP00000419509.1	F8WF13
ZC3HC1	ENST00000648450.1 linkuse as main transcript	n.*501C>A		splice_region_variant, non_coding_transcript_exon_variant	6/12			ENSP00000498166.1	F8WAU5
ZC3HC1	ENST00000467642.5 linkuse as main transcript	n.*375C>A		3_prime_UTR_variant	5/11	2		ENSP00000419509.1	F8WF13
ZC3HC1	ENST00000648450.1 linkuse as main transcript	n.*501C>A		3_prime_UTR_variant	6/12			ENSP00000498166.1	F8WAU5
ZC3HC1	ENST00000470651.1 linkuse as main transcript	n.*444C>A		downstream_gene_variant		4		ENSP00000420068.1	F8WDK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458554

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725462

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.491C>A (p.P164Q) alteration is located in exon 4 (coding exon 4) of the ZC3HC1 gene. This alteration results from a C to A substitution at nucleotide position 491, causing the proline (P) at amino acid position 164 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

0.82

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.5

M;.;M;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.6

D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.015

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.68

MutPred

0.87

Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.67

MPC

0.83

ClinPred

0.98

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.015

dbscSNV1_RF

Benign

0.35

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over