2-112236583-C-A

Variant names:

• chr2-112236583-C-A
• NM_032494.3:c.483G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032494.3(ZC3H8):​c.483G>T​(p.Arg161Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZC3H8 NM_032494.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.604

Genes affected

ZC3H8 (HGNC:30941): (zinc finger CCCH-type containing 8) Enables RNA binding activity. Involved in several processes, including positive regulation of thymocyte apoptotic process; regulation of transcription, DNA-templated; and snRNA transcription. Located in Cajal body; histone locus body; and transcriptionally active chromatin. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

FBLN7 (HGNC:26740): (fibulin 7) Predicted to enable calcium ion binding activity; heparan sulfate proteoglycan binding activity; and heparin binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within positive regulation of biomineralization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05208847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H8	NM_032494.3	c.483G>T	p.Arg161Ser	missense_variant	Exon 4 of 9	ENST00000409573.7	NP_115883.2
ZC3H8	XR_001738994.2	n.544G>T		non_coding_transcript_exon_variant	Exon 4 of 9
FBLN7	XR_007069507.1	n.10509-2538C>A		intron_variant	Intron 8 of 9
FBLN7	XR_007069508.1	n.10508+5698C>A		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H8	ENST00000409573.7	c.483G>T	p.Arg161Ser	missense_variant	Exon 4 of 9	5	NM_032494.3	ENSP00000386488.1
ZC3H8	ENST00000466259.1	n.390G>T		non_coding_transcript_exon_variant	Exon 2 of 4	2
ZC3H8	ENST00000474234.5	n.663G>T		non_coding_transcript_exon_variant	Exon 5 of 7	5
ZC3H8	ENST00000464305.1	n.*3G>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.483G>T (p.R161S) alteration is located in exon 4 (coding exon 4) of the ZC3H8 gene. This alteration results from a G to T substitution at nucleotide position 483, causing the arginine (R) at amino acid position 161 to be replaced by a serine (S). 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	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.015	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.28	N;N;.
REVEL	Benign	0.0050
Sift	Benign	0.51	T;T;.
Sift4G	Benign	0.73	T;T;T
Polyphen		0.041	B;B;.
Vest4		0.14
MutPred		0.25		Loss of MoRF binding (P = 0.0156);Loss of MoRF binding (P = 0.0156);Loss of MoRF binding (P = 0.0156);
MVP		0.067
MPC		0.19
ClinPred		0.048	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-112994160;