19-47066569-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_015168.2(ZC3H4):c.3699C>T(p.Thr1233=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,583,926 control chromosomes in the GnomAD database, including 1,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (316 hom., cov: 33)
  • Exomes 𝑓: 0.015 (798 hom.)
• Consequence: ZC3H4 NM_015168.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.06

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-47066569-G-A is Benign according to our data. Variant chr19-47066569-G-A is described in ClinVar as [Benign]. Clinvar id is 3038500.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H4	NM_015168.2	c.3699C>T	p.Thr1233=	synonymous_variant	15/15	ENST00000253048.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H4	ENST00000253048.10	c.3699C>T	p.Thr1233=	synonymous_variant	15/15	1	NM_015168.2	P1
ZC3H4	ENST00000601973.1	c.2520C>T	p.Thr840=	synonymous_variant	8/8	5
ZC3H4	ENST00000594019.5	n.1549C>T		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.0422 AC: 6426 AN: 152192 Hom.: 317 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.0492

Gnomad SAS AF: 0.0989

Gnomad FIN AF: 0.00790

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.0401

GnomAD3 exomes AF: 0.0299 AC: 6241 AN: 209004 Hom.: 259 AF XY: 0.0307 AC XY: 3504 AN XY: 114152

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.0576

Gnomad SAS exome AF: 0.0982

Gnomad FIN exome AF: 0.00835

Gnomad NFE exome AF: 0.00671

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0152 AC: 21798 AN: 1431616 Hom.: 798 Cov.: 33 AF XY: 0.0171 AC XY: 12081 AN XY: 708290

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.0517

Gnomad4 SAS exome AF: 0.0919

Gnomad4 FIN exome AF: 0.00783

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0423 AC: 6436 AN: 152310 Hom.: 316 Cov.: 33 AF XY: 0.0434 AC XY: 3229 AN XY: 74476

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.0489

Gnomad4 SAS AF: 0.0990

Gnomad4 FIN AF: 0.00790

Gnomad4 NFE AF: 0.00570

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.0207 Hom.: 33

Bravo AF: 0.0451

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZC3H4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2020

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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0070
Dann	Benign	0.50

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: rs3810292; hg19: chr19-47569826; COSMIC: COSV53413193;