Genetic Variant ZC3HC1:p.Arg363Leu (chr7-130023656-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016478.5(ZC3HC1):c.1088G>T(p.Arg363Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZC3HC1
NM_016478.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

232 publications found

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:

UBE2H-DT (HGNC:55615): (UBE2H divergent transcript)

UBE2H-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3HC1	NM_016478.5 link	c.1088G>T	p.Arg363Leu	missense_variant	Exon 8 of 10	ENST00000358303.9	NP_057562.3	Q86WB0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZC3HC1	ENST00000358303.9 link	c.1088G>T	p.Arg363Leu	missense_variant	Exon 8 of 10	1	NM_016478.5	ENSP00000351052.4	Q86WB0-1
ZC3HC1	ENST00000481503.5 link	c.959G>T	p.Arg320Leu	missense_variant	Exon 8 of 10	5		ENSP00000418533.1	C9J0I9
ZC3HC1	ENST00000467642.5 link	n.*972G>T		non_coding_transcript_exon_variant	Exon 9 of 11	2		ENSP00000419509.1	F8WF13
ZC3HC1	ENST00000470651.2 link	n.*1041G>T		non_coding_transcript_exon_variant	Exon 9 of 11	4		ENSP00000420068.1	F8WDK5
ZC3HC1	ENST00000484432.2 link	n.*902G>T		non_coding_transcript_exon_variant	Exon 8 of 10	4		ENSP00000417217.1	F8WAU5
ZC3HC1	ENST00000648450.1 link	n.*1098G>T		non_coding_transcript_exon_variant	Exon 10 of 12			ENSP00000498166.1	F8WAU5
ZC3HC1	ENST00000467642.5 link	n.*972G>T		3_prime_UTR_variant	Exon 9 of 11	2		ENSP00000419509.1	F8WF13
ZC3HC1	ENST00000470651.2 link	n.*1041G>T		3_prime_UTR_variant	Exon 9 of 11	4		ENSP00000420068.1	F8WDK5
ZC3HC1	ENST00000484432.2 link	n.*902G>T		3_prime_UTR_variant	Exon 8 of 10	4		ENSP00000417217.1	F8WAU5
ZC3HC1	ENST00000648450.1 link	n.*1098G>T		3_prime_UTR_variant	Exon 10 of 12			ENSP00000498166.1	F8WAU5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251378

AF XY:

0.00

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.2

M;.;.

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

D;.;D

Vest4

0.62

MutPred

0.22

Gain of catalytic residue at R363 (P = 0.0094);.;.;

MVP

0.65

MPC

0.88

ClinPred

0.96

GERP RS

5.5

Varity_R

0.29

gMVP

0.33

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over