Variant 4-25312912-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024936.3(ZCCHC4):c.103G>A(p.Val35Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ZCCHC4
NM_024936.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.262

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051796943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3 linkuse as main transcript	c.103G>A	p.Val35Ile	missense_variant	1/13	ENST00000302874.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9 linkuse as main transcript	c.103G>A	p.Val35Ile	missense_variant	1/13	1	NM_024936.3	P1	Q9H5U6-1
ZCCHC4	ENST00000505451.5 linkuse as main transcript	n.128G>A		non_coding_transcript_exon_variant	1/9	1
ZCCHC4	ENST00000507760.5 linkuse as main transcript	c.103G>A	p.Val35Ile	missense_variant, NMD_transcript_variant	1/9	1			Q9H5U6-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

248816

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1460476

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000842

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.103G>A (p.V35I) alteration is located in exon 1 (coding exon 1) of the ZCCHC4 gene. This alteration results from a G to A substitution at nucleotide position 103, causing the valine (V) at amino acid position 35 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.73

Cadd

Benign

6.2

Dann

Benign

0.95

DEOGEN2

Benign

0.0038

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00033

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.37

N;.

REVEL

Benign

0.0040

Sift

Benign

0.19

T;.

Sift4G

Benign

0.18

T;T

Polyphen

0.043

B;.

Vest4

0.21

MVP

0.014

MPC

0.067

ClinPred

0.021

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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