Genetic Variant ZCCHC4:p.Arg178Trp (chr4-25333385-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024936.3(ZCCHC4):c.532C>T(p.Arg178Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ZCCHC4
NM_024936.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

ZCCHC4 (HGNC:22917): (zinc finger CCHC-type containing 4) Enables S-adenosyl-L-methionine binding activity; rRNA (adenine-N6-)-methyltransferase activity; and zinc ion binding activity. Involved in positive regulation of translation and rRNA methylation. Located in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC4	NM_024936.3 link	c.532C>T	p.Arg178Trp	missense_variant	Exon 4 of 13	ENST00000302874.9	NP_079212.2	Q9H5U6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZCCHC4	ENST00000302874.9 link	c.532C>T	p.Arg178Trp	missense_variant	Exon 4 of 13	1	NM_024936.3	ENSP00000303468.4	Q9H5U6-1
ZCCHC4	ENST00000505451.5 link	n.557C>T		non_coding_transcript_exon_variant	Exon 4 of 9	1
ZCCHC4	ENST00000507760.5 link	n.532C>T		non_coding_transcript_exon_variant	Exon 4 of 9	1		ENSP00000422115.1	Q9H5U6-2
ZCCHC4	ENST00000505412.1 link	c.124C>T	p.Arg42Trp	missense_variant	Exon 1 of 10	3		ENSP00000422269.1	H0Y8V8

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249506

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000497

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.532C>T (p.R178W) alteration is located in exon 4 (coding exon 4) of the ZCCHC4 gene. This alteration results from a C to T substitution at nucleotide position 532, causing the arginine (R) at amino acid position 178 to be replaced by a tryptophan (W). 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

Uncertain

0.42

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.082

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.43

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.83

MutPred

0.57

Gain of catalytic residue at Q181 (P = 0.1588);

MVP

0.19

MPC

0.44

ClinPred

0.97

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.74

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