8-143440074-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015117.3(ZC3H3):​c.2782C>G​(p.Arg928Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R928W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZC3H3 NM_015117.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17140642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3	c.2782C>G	p.Arg928Gly	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>G	p.Arg928Gly	missense_variant	Exon 11 of 12	1	NM_015117.3	ENSP00000262577.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1438192 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712898

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 41018

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39012

South Asian (SAS) AF: 0.00 AC: 0 AN: 83166

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: 0.00000272 AC: 3 AN: 1101492

Other (OTH) AF: 0.00 AC: 0 AN: 59410

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.047
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.40	T
Polyphen		0.45	B
Vest4		0.24
MutPred		0.23		Loss of methylation at R928 (P = 0.0143);
MVP		0.043
ClinPred		0.47	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.20
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;