8-143440074-G-A

Variant names:

• chr8-143440074-G-A
• rs781724908
• NM_015117.3:c.2782C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015117.3(ZC3H3):​c.2782C>T​(p.Arg928Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,590,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R928Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ZC3H3 NM_015117.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.072778136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3	c.2782C>T	p.Arg928Trp	missense_variant	Exon 11 of 12	ENST00000262577.6	NP_055932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H3	ENST00000262577.6	c.2782C>T	p.Arg928Trp	missense_variant	Exon 11 of 12	1	NM_015117.3	ENSP00000262577.5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151864 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000977 AC: 21 AN: 214918 AF XY: 0.0000942

Gnomad AFR exome AF: 0.0000798

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000618

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 72 AN: 1438190 Hom.: 0 Cov.: 32 AF XY: 0.0000561 AC XY: 40 AN XY: 712896

African (AFR) AF: 0.0000602 AC: 2 AN: 33216

American (AMR) AF: 0.0000975 AC: 4 AN: 41018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39012

South Asian (SAS) AF: 0.000493 AC: 41 AN: 83164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.0000182 AC: 20 AN: 1101492

Other (OTH) AF: 0.0000673 AC: 4 AN: 59410

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151982 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.0000242 AC: 1 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67934

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000355 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000746 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2782C>T (p.R928W) alteration is located in exon 11 (coding exon 11) of the ZC3H3 gene. This alteration results from a C to T substitution at nucleotide position 2782, causing the arginine (R) at amino acid position 928 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.057
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.0060	B
Vest4		0.29
MutPred		0.32		Loss of methylation at R928 (P = 0.0143);
MVP		0.043
ClinPred		0.094	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.21
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs781724908; hg19: chr8-144522244;