4-25362237-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024936.3(ZCCHC4):c.1145C>T(p.Pro382Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,610,652 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P382R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (75 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (82 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Benign criteria provided, single submitter B: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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005337119).
• BP6: Variant 4-25362237-C-T is Benign according to our data. Variant chr4-25362237-C-T is described in ClinVar as [Benign]. Clinvar id is 775952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3	c.1145C>T	p.Pro382Leu	missense_variant	10/13	ENST00000302874.9
ZCCHC4	XM_011513835.3	c.1190C>T	p.Pro397Leu	missense_variant	11/14
ZCCHC4	XM_017008129.3	c.893C>T	p.Pro298Leu	missense_variant	8/11
ZCCHC4	XR_925324.4	n.1226C>T		non_coding_transcript_exon_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.1145C>T	p.Pro382Leu	missense_variant	10/13	1	NM_024936.3	P1
ZCCHC4	ENST00000507760.5	c.*130C>T		3_prime_UTR_variant, NMD_transcript_variant	7/9	1
ZCCHC4	ENST00000505412.1	c.740C>T	p.Pro247Leu	missense_variant	7/10	3
ZCCHC4	ENST00000508058.1	n.284C>T		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2603 AN: 152094 Hom.: 75 Cov.: 33

Gnomad AFR AF: 0.0579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00847

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00561 AC: 1393 AN: 248390 Hom.: 32 AF XY: 0.00479 AC XY: 646 AN XY: 134838

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.00161

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00251 AC: 3664 AN: 1458440 Hom.: 82 Cov.: 29 AF XY: 0.00232 AC XY: 1683 AN XY: 725596

Gnomad4 AFR exome AF: 0.0656

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0152

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.0172 AC: 2612 AN: 152212 Hom.: 75 Cov.: 33 AF XY: 0.0168 AC XY: 1254 AN XY: 74422

Gnomad4 AFR AF: 0.0579

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00849

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00317 Hom.: 18

Bravo AF: 0.0201

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0614 AC: 227

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.00653 AC: 789

Asia WGS AF: 0.0100 AC: 35 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	5.1
Dann	Benign	0.18
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.13
Sift	Benign	0.38	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.076
MPC		0.082
ClinPred		0.0041	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.060

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;