4-25362237-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024936.3(ZCCHC4):c.1145C>G(p.Pro382Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. P382L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11926007).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3	c.1145C>G	p.Pro382Arg	missense_variant	10/13	ENST00000302874.9
ZCCHC4	XM_011513835.3	c.1190C>G	p.Pro397Arg	missense_variant	11/14
ZCCHC4	XM_017008129.3	c.893C>G	p.Pro298Arg	missense_variant	8/11
ZCCHC4	XR_925324.4	n.1226C>G		non_coding_transcript_exon_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.1145C>G	p.Pro382Arg	missense_variant	10/13	1	NM_024936.3	P1
ZCCHC4	ENST00000507760.5	c.*130C>G		3_prime_UTR_variant, NMD_transcript_variant	7/9	1
ZCCHC4	ENST00000505412.1	c.740C>G	p.Pro247Arg	missense_variant	7/10	3
ZCCHC4	ENST00000508058.1	n.284C>G		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458470 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.1145C>G (p.P382R) alteration is located in exon 10 (coding exon 10) of the ZCCHC4 gene. This alteration results from a C to G substitution at nucleotide position 1145, causing the proline (P) at amino acid position 382 to be replaced by an arginine (R). 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	0.073
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.8
Dann	Benign	0.23
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.092
Sift	Benign	0.54	T
Sift4G	Benign	0.53	T
Polyphen		0.024	B
Vest4		0.12
MutPred		0.27		Loss of loop (P = 0.0512);
MVP		0.092
MPC		0.085
ClinPred		0.099	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.24

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: rs3752873; hg19: chr4-25363859;