8-143440954-G-A

Variant names:

• chr8-143440954-G-A
• rs751215773
• NM_015117.3:c.2474C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015117.3(ZC3H3):​c.2474C>T​(p.Ser825Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,435,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ZC3H3 NM_015117.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.775
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04937619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3	c.2474C>T	p.Ser825Leu	missense_variant	Exon 10 of 12	ENST00000262577.6	NP_055932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H3	ENST00000262577.6	c.2474C>T	p.Ser825Leu	missense_variant	Exon 10 of 12	1	NM_015117.3	ENSP00000262577.5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152182 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000298 AC: 3 AN: 100634 AF XY: 0.00

Gnomad AFR exome AF: 0.000256

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000366 AC: 47 AN: 1283012 Hom.: 0 Cov.: 31 AF XY: 0.0000367 AC XY: 23 AN XY: 626252

African (AFR) AF: 0.000117 AC: 3 AN: 25694

American (AMR) AF: 0.00 AC: 0 AN: 19478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18420

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31052

South Asian (SAS) AF: 0.0000170 AC: 1 AN: 58994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 0.0000388 AC: 40 AN: 1031348

Other (OTH) AF: 0.0000381 AC: 2 AN: 52512

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152300 Hom.: 0 Cov.: 35 AF XY: 0.0000806 AC XY: 6 AN XY: 74472

African (AFR) AF: 0.000241 AC: 10 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2474C>T (p.S825L) alteration is located in exon 10 (coding exon 10) of the ZC3H3 gene. This alteration results from a C to T substitution at nucleotide position 2474, causing the serine (S) at amino acid position 825 to be replaced by a leucine (L). 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	0.089
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.78
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.026
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.035	D
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.26		Loss of phosphorylation at S825 (P = 0.0042);
MVP		0.043
ClinPred		0.061	T
GERP RS		0.50
Varity_R		0.083
gMVP		0.31
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs751215773; hg19: chr8-144523124; COSMIC: COSV105004441;