4-25314054-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_024936.3(ZCCHC4):​c.136C>T​(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,386,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000011 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ZCCHC4
NM_024936.3 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZCCHC4NM_024936.3 linkc.136C>T p.Leu46Phe missense_variant Exon 2 of 13 ENST00000302874.9 NP_079212.2 Q9H5U6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZCCHC4ENST00000302874.9 linkc.136C>T p.Leu46Phe missense_variant Exon 2 of 13 1 NM_024936.3 ENSP00000303468.4 Q9H5U6-1
ZCCHC4ENST00000505451.5 linkn.161C>T non_coding_transcript_exon_variant Exon 2 of 9 1
ZCCHC4ENST00000507760.5 linkn.136C>T non_coding_transcript_exon_variant Exon 2 of 9 1 ENSP00000422115.1 Q9H5U6-2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
144804
Hom.:
0
Cov.:
31
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000200
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000841
AC:
2
AN:
237746
Hom.:
0
AF XY:
0.0000155
AC XY:
2
AN XY:
129364
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000119
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000108
AC:
15
AN:
1386422
Hom.:
0
Cov.:
29
AF XY:
0.0000130
AC XY:
9
AN XY:
692638
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000358
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.50e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000690
AC:
1
AN:
144902
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
69904
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000200
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
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
Jan 09, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.136C>T (p.L46F) alteration is located in exon 2 (coding exon 2) of the ZCCHC4 gene. This alteration results from a C to T substitution at nucleotide position 136, causing the leucine (L) at amino acid position 46 to be replaced by a phenylalanine (F). 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
Pathogenic
0.62
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.16
T;T
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-3.6
D;.
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;.
Vest4
0.69
MutPred
0.74
Loss of stability (P = 0.1175);.;
MVP
0.30
MPC
0.45
ClinPred
0.97
D
GERP RS
5.8
Varity_R
0.85
gMVP
0.62

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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.

Other links and lift over

dbSNP: rs1338294731; hg19: chr4-25315676; API