4-25333328-C-A

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.475C>A(p.Gln159Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,060 control chromosomes in the GnomAD database, including 26 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 0.0068 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10

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=0.0045552254).
• BP6: Variant 4-25333328-C-A is Benign according to our data. Variant chr4-25333328-C-A is described in ClinVar as [Benign]. Clinvar id is 720330.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00678 (1032/152244) while in subpopulation AFR AF= 0.0233 (969/41538). AF 95% confidence interval is 0.0221. There are 11 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3	c.475C>A	p.Gln159Lys	missense_variant	4/13	ENST00000302874.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.475C>A	p.Gln159Lys	missense_variant	4/13	1	NM_024936.3	P1
ZCCHC4	ENST00000505451.5	n.500C>A		non_coding_transcript_exon_variant	4/9	1
ZCCHC4	ENST00000507760.5	c.475C>A	p.Gln159Lys	missense_variant, NMD_transcript_variant	4/9	1
ZCCHC4	ENST00000505412.1	c.70C>A	p.Gln24Lys	missense_variant	1/10	3

Frequencies

GnomAD3 genomes AF: 0.00673 AC: 1024 AN: 152126 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00183 AC: 457 AN: 249526 Hom.: 7 AF XY: 0.00134 AC XY: 181 AN XY: 135374

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000790 AC: 1155 AN: 1461816 Hom.: 15 Cov.: 31 AF XY: 0.000701 AC XY: 510 AN XY: 727202

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00678 AC: 1032 AN: 152244 Hom.: 11 Cov.: 33 AF XY: 0.00648 AC XY: 482 AN XY: 74436

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00139 Hom.: 4

Bravo AF: 0.00822

ESP6500AA AF: 0.0250 AC: 95

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00220 AC: 266

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.078
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Benign	0.93
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.036
Sift	Benign	0.10	T
Sift4G	Benign	0.23	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.055
MPC		0.10
ClinPred		0.0043	T
GERP RS		4.1
Varity_R		0.37
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77036618; hg19: chr4-25334950;