chr8-143440304-G-A

Variant names:

• chr8-143440304-G-A
• rs141703643
• NM_015117.3:c.2552C>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.2552C>T​(p.Ala851Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,561,102 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. 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. A851G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ZC3H3 NM_015117.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.528
• 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=0.0238972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3	c.2552C>T	p.Ala851Val	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.2552C>T	p.Ala851Val	missense_variant	Exon 11 of 12	1	NM_015117.3	ENSP00000262577.5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 25 AN: 195158 AF XY: 0.0000854

Gnomad AFR exome AF: 0.000160

Gnomad AMR exome AF: 0.000510

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000195

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.000410

GnomAD4 exome AF: 0.0000291 AC: 41 AN: 1408774 Hom.: 0 Cov.: 34 AF XY: 0.0000187 AC XY: 13 AN XY: 694002

African (AFR) AF: 0.0000306 AC: 1 AN: 32682

American (AMR) AF: 0.000440 AC: 17 AN: 38602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23972

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38504

South Asian (SAS) AF: 0.0000499 AC: 4 AN: 80112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1082898

Other (OTH) AF: 0.0000688 AC: 4 AN: 58124

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74480

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000499 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2552C>T (p.A851V) 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 2552, causing the alanine (A) at amino acid position 851 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.5
DANN	Benign	0.95
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		-0.53
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.034
Sift	Uncertain	0.018	D
Sift4G	Benign	0.28	T
Polyphen		0.019	B
Vest4		0.15
MVP		0.043
ClinPred		0.021	T
GERP RS		1.9
Varity_R		0.034
gMVP		0.39
Mutation Taster		=97/3	polymorphism

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: rs141703643; hg19: chr8-144522474;