7-130023656-C-T

Variant names:

• chr7-130023656-C-T
• rs11556924
• NM_016478.5:c.1088G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016478.5(ZC3HC1):​c.1088G>A​(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,613,734 control chromosomes in the GnomAD database, including 100,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 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: 𝑓 0.26 (6492 hom., cov: 32)
  • Exomes 𝑓: 0.35 (94069 hom.)
• Consequence: ZC3HC1 NM_016478.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 232 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018992424).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016478.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3HC1	NM_016478.5	MANE Select	c.1088G>A	p.Arg363His	missense	Exon 8 of 10	NP_057562.3
	ZC3HC1	NM_001282190.2		c.1025G>A	p.Arg342His	missense	Exon 9 of 11	NP_001269119.1	Q86WB0-2
	ZC3HC1	NM_001363701.1		c.959G>A	p.Arg320His	missense	Exon 8 of 10	NP_001350630.1	C9J0I9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3HC1	ENST00000358303.9	TSL:1 MANE Select	c.1088G>A	p.Arg363His	missense	Exon 8 of 10	ENSP00000351052.4	Q86WB0-1
	ZC3HC1	ENST00000481503.5	TSL:5	c.959G>A	p.Arg320His	missense	Exon 8 of 10	ENSP00000418533.1	C9J0I9
	ZC3HC1	ENST00000467642.5	TSL:2	n.*972G>A		non_coding_transcript_exon	Exon 9 of 11	ENSP00000419509.1	F8WF13

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39248 AN: 151858 Hom.: 6494 Cov.: 32

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.275 AC: 69236 AN: 251378 AF XY: 0.282

Gnomad AFR exome AF: 0.0669

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.0572

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.376

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.346 AC: 505616 AN: 1461758 Hom.: 94069 Cov.: 48 AF XY: 0.343 AC XY: 249277 AN XY: 727172

African (AFR) AF: 0.0601 AC: 2011 AN: 33480

American (AMR) AF: 0.170 AC: 7608 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 10160 AN: 26134

East Asian (EAS) AF: 0.0394 AC: 1565 AN: 39700

South Asian (SAS) AF: 0.198 AC: 17034 AN: 86242

European-Finnish (FIN) AF: 0.321 AC: 17153 AN: 53418

Middle Eastern (MID) AF: 0.248 AC: 1430 AN: 5768

European-Non Finnish (NFE) AF: 0.386 AC: 429214 AN: 1111900

Other (OTH) AF: 0.322 AC: 19441 AN: 60392

GnomAD4 genome AF: 0.258 AC: 39238 AN: 151976 Hom.: 6492 Cov.: 32 AF XY: 0.253 AC XY: 18780 AN XY: 74262

African (AFR) AF: 0.0744 AC: 3085 AN: 41478

American (AMR) AF: 0.223 AC: 3400 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1321 AN: 3470

East Asian (EAS) AF: 0.0536 AC: 278 AN: 5184

South Asian (SAS) AF: 0.183 AC: 882 AN: 4814

European-Finnish (FIN) AF: 0.312 AC: 3277 AN: 10514

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26002 AN: 67948

Other (OTH) AF: 0.261 AC: 549 AN: 2106

Alfa AF: 0.335 Hom.: 40208

Bravo AF: 0.244

TwinsUK AF: 0.396 AC: 1468

ALSPAC AF: 0.399 AC: 1537

ESP6500AA AF: 0.0815 AC: 359

ESP6500EA AF: 0.383 AC: 3290

ExAC AF: 0.273 AC: 33132

Asia WGS AF: 0.134 AC: 465 AN: 3478

EpiCase AF: 0.380

EpiControl AF: 0.369

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.0
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.36
MPC		0.91
ClinPred		0.019	T
GERP RS		5.5
Varity_R		0.18
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11556924; hg19: chr7-129663496; COSMIC: COSV61299949; COSMIC: COSV61299949;