chr7-130022356-T-A

Position:

• chr7-130022356-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016478.5(ZC3HC1):​c.1403A>T​(p.His468Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: ZC3HC1 NM_016478.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.693

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.124432445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3HC1	NM_016478.5	c.1403A>T	p.His468Leu	missense_variant	9/10	ENST00000358303.9	NP_057562.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3HC1	ENST00000358303.9	c.1403A>T	p.His468Leu	missense_variant	9/10	1	NM_016478.5	ENSP00000351052.4
ZC3HC1	ENST00000481503.5	c.1274A>T	p.His425Leu	missense_variant	9/10	5		ENSP00000418533.1
ZC3HC1	ENST00000467642.5	n.*1287A>T		non_coding_transcript_exon_variant	10/11	2		ENSP00000419509.1
ZC3HC1	ENST00000648450.1	n.*1413A>T		non_coding_transcript_exon_variant	11/12			ENSP00000498166.1
ZC3HC1	ENST00000467642.5	n.*1287A>T		3_prime_UTR_variant	10/11	2		ENSP00000419509.1
ZC3HC1	ENST00000648450.1	n.*1413A>T		3_prime_UTR_variant	11/12			ENSP00000498166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 17, 2023

The c.1403A>T (p.H468L) alteration is located in exon 9 (coding exon 9) of the ZC3HC1 gene. This alteration results from a A to T substitution at nucleotide position 1403, causing the histidine (H) at amino acid position 468 to be replaced by a leucine (L). 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	0.095
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.0065	T;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;D;N;N
REVEL	Benign	0.11
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.80	T;T;T;T
Polyphen		0.036	B;.;B;B
Vest4		0.30
MutPred		0.23		Gain of helix (P = 0.0425);.;.;.;
MVP		0.56
MPC		0.29
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.093
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-129662196;