rs3750208

chr8-143538865-G-A

Variant summary

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

The NM_015117.3(ZC3H3):c.502C>T(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,612,228 control chromosomes in the GnomAD database, including 15,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1378 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13801 hom.)
• Consequence: ZC3H3 NM_015117.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.580

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=8.5929036E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H3	NM_015117.3	c.502C>T	p.Arg168Trp	missense_variant	2/12	ENST00000262577.6
ZC3H3	XM_011516943.3	c.502C>T	p.Arg168Trp	missense_variant	2/10
ZC3H3	XM_011516944.3	c.502C>T	p.Arg168Trp	missense_variant	2/5
ZC3H3	XR_928313.4	n.528C>T		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H3	ENST00000262577.6	c.502C>T	p.Arg168Trp	missense_variant	2/12	1	NM_015117.3	P1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18080 AN: 152184 Hom.: 1371 Cov.: 34

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.138 AC: 34021 AN: 247154 Hom.: 2524 AF XY: 0.141 AC XY: 18911 AN XY: 134580

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.135 AC: 196820 AN: 1459926 Hom.: 13801 Cov.: 80 AF XY: 0.136 AC XY: 98940 AN XY: 726230

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.119 AC: 18110 AN: 152302 Hom.: 1378 Cov.: 34 AF XY: 0.125 AC XY: 9337 AN XY: 74468

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.105

Alfa AF: 0.129 Hom.: 2652

Bravo AF: 0.109

TwinsUK AF: 0.132 AC: 491

ALSPAC AF: 0.140 AC: 538

ESP6500AA AF: 0.0391 AC: 172

ESP6500EA AF: 0.129 AC: 1105

ExAC AF: 0.133 AC: 16142

Asia WGS AF: 0.160 AC: 555 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.131

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.00086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.050
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.0	B
Vest4		0.066
ClinPred		0.015	T
GERP RS		2.7
Varity_R		0.044
gMVP		0.13

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: rs3750208; hg19: chr8-144621035; COSMIC: COSV52791762; COSMIC: COSV52791762;