Variant 7-130029016-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016478.5(ZC3HC1):c.507G>A(p.Met169Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,612,878 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

ZC3HC1
NM_016478.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029472321).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3HC1	NM_016478.5 link	c.507G>A	p.Met169Ile	missense_variant	5/10	ENST00000358303.9	NP_057562.3	Q86WB0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZC3HC1	ENST00000358303.9 link	c.507G>A	p.Met169Ile	missense_variant	5/10	1	NM_016478.5	ENSP00000351052.4	Q86WB0-1
ZC3HC1	ENST00000481503.5 link	c.507G>A	p.Met169Ile	missense_variant	5/10	5		ENSP00000418533.1	C9J0I9
ZC3HC1	ENST00000467642.5 link	n.*391G>A		non_coding_transcript_exon_variant	6/11	2		ENSP00000419509.1	F8WF13
ZC3HC1	ENST00000648450.1 link	n.*517G>A		non_coding_transcript_exon_variant	7/12			ENSP00000498166.1	F8WAU5
ZC3HC1	ENST00000467642.5 link	n.*391G>A		3_prime_UTR_variant	6/11	2		ENSP00000419509.1	F8WF13
ZC3HC1	ENST00000648450.1 link	n.*517G>A		3_prime_UTR_variant	7/12			ENSP00000498166.1	F8WAU5

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00165

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000757

AC:

190

AN:

251014

Hom.:

AF XY:

0.000656

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00165

AC:

2411

AN:

1460726

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1149

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000244

Gnomad4 NFE exome

AF:

0.00210

Gnomad4 OTH exome

AF:

0.000829

GnomAD4 genome

AF:

0.000927

AC:

141

AN:

152152

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000531

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.000725

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00160

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

Dec 09, 2023

The c.507G>A (p.M169I) alteration is located in exon 5 (coding exon 5) of the ZC3HC1 gene. This alteration results from a G to A substitution at nucleotide position 507, causing the methionine (M) at amino acid position 169 to be replaced by an isoleucine (I). 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

0.26

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0035

T;.;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.079

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.029

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.14

N;.;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.065

Sift

Benign

0.29

T;T;T;T

Sift4G

Benign

0.30

T;T;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.24

MutPred

0.54

Gain of catalytic residue at P171 (P = 0.0558);.;Gain of catalytic residue at P171 (P = 0.0558);Gain of catalytic residue at P171 (P = 0.0558);

MVP

0.38

MPC

0.26

ClinPred

0.018

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.051

gMVP

0.23

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

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