chr4-25314054-C-T

Variant names:

• chr4-25314054-C-T
• rs1338294731
• NM_024936.3:c.136C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024936.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC4	NM_024936.3	MANE Select	c.136C>T	p.Leu46Phe	missense	Exon 2 of 13	NP_079212.2
	ZCCHC4	NM_001318148.2		c.136C>T	p.Leu46Phe	missense	Exon 2 of 9	NP_001305077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZCCHC4	ENST00000302874.9	TSL:1 MANE Select	c.136C>T	p.Leu46Phe	missense	Exon 2 of 13	ENSP00000303468.4	Q9H5U6-1
	ZCCHC4	ENST00000505451.5	TSL:1	n.161C>T		non_coding_transcript_exon	Exon 2 of 9
	ZCCHC4	ENST00000507760.5	TSL:1	n.136C>T		non_coding_transcript_exon	Exon 2 of 9	ENSP00000422115.1	Q9H5U6-2

Frequencies

GnomAD3 genomes AF: 0.00000691 AC: 1 AN: 144804 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00000841 AC: 2 AN: 237746 AF XY: 0.0000155

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31534

American (AMR) AF: 0.00 AC: 0 AN: 40940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24960

East Asian (EAS) AF: 0.000358 AC: 14 AN: 39072

South Asian (SAS) AF: 0.00 AC: 0 AN: 81584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052944

Other (OTH) AF: 0.00 AC: 0 AN: 57526

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39436

American (AMR) AF: 0.00 AC: 0 AN: 14340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4990

South Asian (SAS) AF: 0.00 AC: 0 AN: 4618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66588

Other (OTH) AF: 0.00 AC: 0 AN: 2004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	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
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs1338294731; hg19: chr4-25315676;