rs4873802

Variant names:

• chr8-143538685-C-A
• rs4873802
• NM_015117.3:c.682G>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015117.3. 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
	ZC3H3	NM_015117.3	MANE Select	c.682G>T	p.Ala228Ser	missense	Exon 2 of 12	NP_055932.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H3	ENST00000262577.6	TSL:1 MANE Select	c.682G>T	p.Ala228Ser	missense	Exon 2 of 12	ENSP00000262577.5
	ZC3H3	ENST00000875766.1		c.682G>T	p.Ala228Ser	missense	Exon 2 of 13	ENSP00000545825.1
	ZC3H3	ENST00000932295.1		c.682G>T	p.Ala228Ser	missense	Exon 2 of 11	ENSP00000602354.1

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

GnomAD2 exomes AF: 0.194 AC: 47097 AN: 242712 AF XY: 0.197

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 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

African (AFR) AF: 0.0624 AC: 2088 AN: 33478

American (AMR) AF: 0.245 AC: 10931 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 6132 AN: 26114

East Asian (EAS) AF: 0.110 AC: 4369 AN: 39692

South Asian (SAS) AF: 0.234 AC: 20146 AN: 86200

European-Finnish (FIN) AF: 0.234 AC: 11099 AN: 47420

Middle Eastern (MID) AF: 0.253 AC: 1459 AN: 5766

European-Non Finnish (NFE) AF: 0.189 AC: 210592 AN: 1111704

Other (OTH) AF: 0.185 AC: 11141 AN: 60320

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

African (AFR) AF: 0.0634 AC: 2638 AN: 41590

American (AMR) AF: 0.187 AC: 2860 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3472

East Asian (EAS) AF: 0.0846 AC: 438 AN: 5180

South Asian (SAS) AF: 0.237 AC: 1143 AN: 4832

European-Finnish (FIN) AF: 0.234 AC: 2481 AN: 10622

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

European-Non Finnish (NFE) AF: 0.188 AC: 12765 AN: 68008

Other (OTH) AF: 0.173 AC: 366 AN: 2116

Alfa AF: 0.177 Hom.: 6715

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 v4.9

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
PhyloP100		-0.29
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
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: rs4873802; hg19: chr8-144620855; COSMIC: COSV52792974; COSMIC: COSV52792974;