rs3750208

Variant names:

• chr8-143538865-G-A
• rs3750208
• NM_015117.3:c.502C>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.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. 14/21 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 0.12 (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
• Publications: 26 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=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 rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3	c.502C>T	p.Arg168Trp	missense_variant	Exon 2 of 12	ENST00000262577.6	NP_055932.2
ZC3H3	XM_011516943.3	c.502C>T	p.Arg168Trp	missense_variant	Exon 2 of 10		XP_011515245.2
ZC3H3	XM_011516944.3	c.502C>T	p.Arg168Trp	missense_variant	Exon 2 of 5		XP_011515246.2
ZC3H3	XR_928313.4	n.528C>T		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H3	ENST00000262577.6	c.502C>T	p.Arg168Trp	missense_variant	Exon 2 of 12	1	NM_015117.3	ENSP00000262577.5

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

GnomAD2 exomes AF: 0.138 AC: 34021 AN: 247154 AF XY: 0.141

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 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

African (AFR) AF: 0.0365 AC: 1222 AN: 33460

American (AMR) AF: 0.144 AC: 6448 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2893 AN: 26116

East Asian (EAS) AF: 0.123 AC: 4871 AN: 39696

South Asian (SAS) AF: 0.172 AC: 14797 AN: 86212

European-Finnish (FIN) AF: 0.174 AC: 9062 AN: 52116

Middle Eastern (MID) AF: 0.104 AC: 602 AN: 5764

European-Non Finnish (NFE) AF: 0.134 AC: 148891 AN: 1111598

Other (OTH) AF: 0.133 AC: 8034 AN: 60326

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

African (AFR) AF: 0.0432 AC: 1797 AN: 41570

American (AMR) AF: 0.201 AC: 3072 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 398 AN: 3472

East Asian (EAS) AF: 0.132 AC: 683 AN: 5176

South Asian (SAS) AF: 0.174 AC: 838 AN: 4828

European-Finnish (FIN) AF: 0.175 AC: 1859 AN: 10616

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9162 AN: 68012

Other (OTH) AF: 0.105 AC: 222 AN: 2116

Alfa AF: 0.126 Hom.: 3536

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
PhyloP100		0.58
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
Mutation Taster		=94/6	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: rs3750208; hg19: chr8-144621035; COSMIC: COSV52791762; COSMIC: COSV52791762;