rs4873802

Positions:

• chr8-143538685-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015117.3(ZC3H3):​c.682G>T​(p.Ala228Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,607,642 control chromosomes in the GnomAD database, including 30,097 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2192 hom., cov: 34)
  • Exomes 𝑓: 0.19 (27905 hom.)
• Consequence: ZC3H3 NM_015117.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.289

Genes affected

ZC3H3 (HGNC:28972): (zinc finger CCCH-type containing 3) Predicted to enable SMAD binding activity. Involved in regulation of mRNA polyadenylation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003994137).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H3	NM_015117.3	c.682G>T	p.Ala228Ser	missense_variant	2/12	ENST00000262577.6	NP_055932.2
ZC3H3	XM_011516943.3	c.682G>T	p.Ala228Ser	missense_variant	2/10		XP_011515245.2
ZC3H3	XM_011516944.3	c.682G>T	p.Ala228Ser	missense_variant	2/5		XP_011515246.2
ZC3H3	XR_928313.4	n.708G>T		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3H3	ENST00000262577.6	c.682G>T	p.Ala228Ser	missense_variant	2/12	1	NM_015117.3	ENSP00000262577.5

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23820 AN: 152214 Hom.: 2190 Cov.: 34

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0847

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.194 AC: 47097 AN: 242712 Hom.: 5027 AF XY: 0.197 AC XY: 26081 AN XY: 132602

Gnomad AFR exome AF: 0.0628

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.0876

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.191 AC: 277957 AN: 1455310 Hom.: 27905 Cov.: 94 AF XY: 0.193 AC XY: 139503 AN XY: 724226

Gnomad4 AFR exome AF: 0.0624

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.189

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.156 AC: 23820 AN: 152332 Hom.: 2192 Cov.: 34 AF XY: 0.160 AC XY: 11912 AN XY: 74494

Gnomad4 AFR AF: 0.0634

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.0846

Gnomad4 SAS AF: 0.237

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.173

Alfa AF: 0.182 Hom.: 4838

Bravo AF: 0.150

TwinsUK AF: 0.195 AC: 724

ALSPAC AF: 0.191 AC: 736

ESP6500AA AF: 0.0640 AC: 281

ESP6500EA AF: 0.184 AC: 1582

ExAC AF: 0.189 AC: 22886

Asia WGS AF: 0.167 AC: 578 AN: 3478

EpiCase AF: 0.183

EpiControl AF: 0.187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.88
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.026
Sift	Benign	0.18	T
Sift4G	Benign	0.76	T
Polyphen		0.068	B
Vest4		0.043
ClinPred		0.00082	T
GERP RS		0.48
Varity_R		0.034
gMVP		0.088

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

LitVar

Other links and lift over

dbSNP: rs4873802; hg19: chr8-144620855; COSMIC: COSV52792974; COSMIC: COSV52792974;