rs143129413

Positions:

• chr14-88602001-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_024824.5(ZC3H14):​c.1432G>A​(p.Val478Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: ZC3H14 NM_024824.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.124

Genes affected

ZC3H14 (HGNC:20509): (zinc finger CCCH-type containing 14) The protein encoded by this gene is a poly(A)-binding protein that can affect gene expression and poly(A) tail length. The encoded protein may influence mRNA stability, nuclear export, and translation. [provided by RefSeq, May 2016]

ZC3H14 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035073757).
• BP6: Variant 14-88602001-G-A is Benign according to our data. Variant chr14-88602001-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437315.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr14-88602001-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H14	NM_024824.5	c.1432G>A	p.Val478Ile	missense_variant	11/17	ENST00000251038.10	NP_079100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3H14	ENST00000251038.10	c.1432G>A	p.Val478Ile	missense_variant	11/17	1	NM_024824.5	ENSP00000251038.5

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000505 AC: 127 AN: 251364 Hom.: 0 AF XY: 0.000493 AC XY: 67 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000315 AC: 461 AN: 1461854 Hom.: 1 Cov.: 31 AF XY: 0.000307 AC XY: 223 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00811

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74496

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000587 Hom.: 2

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.8
DANN	Benign	0.60
DEOGEN2	Benign	0.036	T;.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.34	T;T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;N;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.080	N;N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.083
MVP		0.043
MPC		0.43
ClinPred		0.0067	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.080

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

Publications

LitVar

Other links and lift over

dbSNP: rs143129413; hg19: chr14-89068345;