chr4-25312855-A-G

Position:

• chr4-25312855-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024936.3(ZCCHC4):​c.46A>G​(p.Ser16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.26

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 (HGNC:):

ACMG classification

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=0.051183015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC4	NM_024936.3	c.46A>G	p.Ser16Gly	missense_variant	1/13	ENST00000302874.9	NP_079212.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.46A>G	p.Ser16Gly	missense_variant	1/13	1	NM_024936.3	ENSP00000303468.4
ZCCHC4	ENST00000505451.5	n.71A>G		non_coding_transcript_exon_variant	1/9	1
ZCCHC4	ENST00000507760.5	n.46A>G		non_coding_transcript_exon_variant	1/9	1		ENSP00000422115.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The c.46A>G (p.S16G) alteration is located in exon 1 (coding exon 1) of the ZCCHC4 gene. This alteration results from a A to G substitution at nucleotide position 46, causing the serine (S) at amino acid position 16 to be replaced by a glycine (G). 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	0.056
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.86
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.0040
Sift	Benign	0.32	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.20		Gain of loop (P = 0.024);
MVP		0.030
MPC		0.076
ClinPred		0.12	T
GERP RS		-3.6
Varity_R		0.064
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-25314477;