4-25312898-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024936.3(ZCCHC4):c.89C>T(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,612,906 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.147

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=0.0030532181).
• BP6: Variant 4-25312898-C-T is Benign according to our data. Variant chr4-25312898-C-T is described in ClinVar as [Benign]. Clinvar id is 791974.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1618/152230) while in subpopulation AFR AF= 0.0374 (1555/41534). AF 95% confidence interval is 0.0359. There are 31 homozygotes in gnomad4. There are 747 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3	c.89C>T	p.Pro30Leu	missense_variant	1/13	ENST00000302874.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.89C>T	p.Pro30Leu	missense_variant	1/13	1	NM_024936.3	P1
ZCCHC4	ENST00000505451.5	n.114C>T		non_coding_transcript_exon_variant	1/9	1
ZCCHC4	ENST00000507760.5	c.89C>T	p.Pro30Leu	missense_variant, NMD_transcript_variant	1/9	1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1615 AN: 152112 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00268 AC: 669 AN: 249262 Hom.: 14 AF XY: 0.00191 AC XY: 258 AN XY: 135282

Gnomad AFR exome AF: 0.0391

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00106 AC: 1542 AN: 1460676 Hom.: 28 Cov.: 31 AF XY: 0.000881 AC XY: 640 AN XY: 726622

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.0106 AC: 1618 AN: 152230 Hom.: 31 Cov.: 32 AF XY: 0.0100 AC XY: 747 AN XY: 74424

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00169 Hom.: 9

Bravo AF: 0.0117

ESP6500AA AF: 0.0339 AC: 141

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00349 AC: 422

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.099
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0049	T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.00066	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.18	N;.
REVEL	Benign	0.054
Sift	Benign	0.18	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;.
Vest4		0.29
MVP		0.055
MPC		0.084
ClinPred		0.0069	T
GERP RS		1.9
Varity_R		0.14
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61743521; hg19: chr4-25314520;