19-47066942-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_015168.2(ZC3H4):c.3326C>T(p.Pro1109Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0183 in 1,594,806 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.013 ( 18 hom., cov: 32)

Exomes 𝑓: 0.019 ( 261 hom. )

Consequence

ZC3H4
NM_015168.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.97

Variant links:

Genes affected

ZC3H4 (HGNC:17808): (zinc finger CCCH-type containing 4) This gene encodes a member of a family of CCCH (C-x8-C-x5-C-x3-H type) zinc finger domain-containing proteins. These zinc finger domains, which coordinate zinc finger binding and are characterized by three cysteine residues and one histidine residue, are nucleic acid-binding. Other family members are known to function in post-transcriptional regulation. [provided by RefSeq, Aug 2011]

ZC3H4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053901076).

BP6

Variant 19-47066942-G-A is Benign according to our data. Variant chr19-47066942-G-A is described in ClinVar as [Benign]. Clinvar id is 3042327.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1956/152306) while in subpopulation NFE AF= 0.0209 (1424/68006). AF 95% confidence interval is 0.02. There are 18 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 1955 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H4	NM_015168.2 linkuse as main transcript	c.3326C>T	p.Pro1109Leu	missense_variant	15/15	ENST00000253048.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZC3H4	ENST00000253048.10 linkuse as main transcript	c.3326C>T	p.Pro1109Leu	missense_variant	15/15	1	NM_015168.2	P1
ZC3H4	ENST00000601973.1 linkuse as main transcript	c.2147C>T	p.Pro716Leu	missense_variant	8/8	5
ZC3H4	ENST00000594019.5 linkuse as main transcript	n.1176C>T		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1955

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0209

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.0128

AC:

2785

AN:

218104

Hom.:

AF XY:

0.0131

AC XY:

1584

AN XY:

120534

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.000297

Gnomad SAS exome

AF:

0.00835

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0189

AC:

27211

AN:

1442500

Hom.:

261

Cov.:

AF XY:

0.0185

AC XY:

13221

AN XY:

716190

show subpopulations

Gnomad4 AFR exome

AF:

0.00235

Gnomad4 AMR exome

AF:

0.00596

Gnomad4 ASJ exome

AF:

0.00262

Gnomad4 EAS exome

AF:

0.000153

Gnomad4 SAS exome

AF:

0.00893

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.0222

Gnomad4 OTH exome

AF:

0.0140

GnomAD4 genome

AF:

0.0128

AC:

1956

AN:

152306

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

906

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00828

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0209

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0121

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00304

AC:

ESP6500EA

AF:

0.0180

AC:

142

ExAC

AF:

0.0123

AC:

1458

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZC3H4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Benign

0.11

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.15

Sift

Uncertain

0.019

Sift4G

Benign

0.17

Polyphen

0.75

Vest4

0.081

MPC

0.11

ClinPred

0.038

GERP RS

5.5

Varity_R

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over