4-25333296-A-G

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.443A>G(p.Asn148Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,088 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (15 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.38

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 (BayesDel_addAF=-0.723988).
• BP6: Variant 4-25333296-A-G is Benign according to our data. Variant chr4-25333296-A-G is described in ClinVar as [Benign]. Clinvar id is 720329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00679 (1034/152248) while in subpopulation AFR AF= 0.0234 (971/41536). AF 95% confidence interval is 0.0222. There are 10 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3	c.443A>G	p.Asn148Ser	missense_variant	4/13	ENST00000302874.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.443A>G	p.Asn148Ser	missense_variant	4/13	1	NM_024936.3	P1
ZCCHC4	ENST00000505451.5	n.468A>G		non_coding_transcript_exon_variant	4/9	1
ZCCHC4	ENST00000507760.5	c.443A>G	p.Asn148Ser	missense_variant, NMD_transcript_variant	4/9	1
ZCCHC4	ENST00000505412.1	c.38A>G	p.Asn13Ser	missense_variant	1/10	3

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1026 AN: 152130 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0233

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: 0.00184 AC: 458 AN: 249506 Hom.: 7 AF XY: 0.00134 AC XY: 181 AN XY: 135354

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: 0.0000353

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000804 AC: 1176 AN: 1461840 Hom.: 15 Cov.: 31 AF XY: 0.000711 AC XY: 517 AN XY: 727224

Gnomad4 AFR exome AF: 0.0274

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: 0.0000297

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152248 Hom.: 10 Cov.: 33 AF XY: 0.00649 AC XY: 483 AN XY: 74436

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00129 Hom.: 3

Bravo AF: 0.00823

ESP6500AA AF: 0.0248 AC: 93

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00222 AC: 268

Asia WGS AF: 0.00173 AC: 6 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	0.070
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	13
Dann	Benign	0.76
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	N
ClinPred		0.050	T
GERP RS		5.8

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: rs77206225; hg19: chr4-25334918; COSMIC: COSV57180941;