Variant 4-25333328-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.10

Variant links:

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]

ZCCHC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC4	NM_024936.3 linkuse as main transcript	c.475C>A	p.Gln159Lys	missense_variant	4/13	ENST00000302874.9	NP_079212.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC4	ENST00000302874.9 linkuse as main transcript	c.475C>A	p.Gln159Lys	missense_variant	4/13	1	NM_024936.3	ENSP00000303468	P1	Q9H5U6-1
ZCCHC4	ENST00000505451.5 linkuse as main transcript	n.500C>A		non_coding_transcript_exon_variant	4/9	1
ZCCHC4	ENST00000507760.5 linkuse as main transcript	c.475C>A	p.Gln159Lys	missense_variant, NMD_transcript_variant	4/9	1		ENSP00000422115		Q9H5U6-2
ZCCHC4	ENST00000505412.1 linkuse as main transcript	c.70C>A	p.Gln24Lys	missense_variant	1/10	3		ENSP00000422269

Frequencies

GnomAD3 genomes

AF:

0.00673

AC:

1024

AN:

152126

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00134

AC XY:

181

AN XY:

135374

show subpopulations

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.:

Cov.:

AF XY:

0.000701

AC XY:

510

AN XY:

727202

show subpopulations

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.:

Cov.:

AF XY:

0.00648

AC XY:

482

AN XY:

74436

show subpopulations

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.:

Bravo

AF:

0.00822

ESP6500AA

AF:

0.0250

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00220

AC:

266

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.051

Eigen_PC

Benign

-0.068

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

REVEL

Benign

0.036

Sift

Benign

0.10

Sift4G

Benign

0.23

Polyphen

0.0020

Vest4

0.20

MVP

0.055

MPC

0.10

ClinPred

0.0043

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over