rs315675

chr4-25362279-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024936.3(ZCCHC4):c.1187T>A(p.Leu396His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,606,556 control chromosomes in the GnomAD database, including 638,947 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.91 (62801 hom., cov: 32)
  • Exomes 𝑓: 0.89 (576146 hom.)
• Consequence: ZCCHC4 NM_024936.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5607344E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZCCHC4	NM_024936.3	c.1187T>A	p.Leu396His	missense_variant	10/13	ENST00000302874.9
ZCCHC4	XM_011513835.3	c.1232T>A	p.Leu411His	missense_variant	11/14
ZCCHC4	XM_017008129.3	c.935T>A	p.Leu312His	missense_variant	8/11
ZCCHC4	XR_925324.4	n.1268T>A		non_coding_transcript_exon_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.1187T>A	p.Leu396His	missense_variant	10/13	1	NM_024936.3	P1
ZCCHC4	ENST00000507760.5	c.*172T>A		3_prime_UTR_variant, NMD_transcript_variant	7/9	1
ZCCHC4	ENST00000505412.1	c.782T>A	p.Leu261His	missense_variant	7/10	3
ZCCHC4	ENST00000508058.1	n.326T>A		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.906 AC: 137922 AN: 152166 Hom.: 62739 Cov.: 32

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.882

Gnomad AMR AF: 0.869

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.920

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.890

Gnomad OTH AF: 0.903

GnomAD3 exomes AF: 0.873 AC: 216607 AN: 248096 Hom.: 94927 AF XY: 0.871 AC XY: 117294 AN XY: 134660

Gnomad AFR exome AF: 0.980

Gnomad AMR exome AF: 0.838

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.770

Gnomad SAS exome AF: 0.832

Gnomad FIN exome AF: 0.921

Gnomad NFE exome AF: 0.888

Gnomad OTH exome AF: 0.877

GnomAD4 exome AF: 0.889 AC: 1293415 AN: 1454272 Hom.: 576146 Cov.: 35 AF XY: 0.887 AC XY: 641505 AN XY: 723400

Gnomad4 AFR exome AF: 0.983

Gnomad4 AMR exome AF: 0.841

Gnomad4 ASJ exome AF: 0.858

Gnomad4 EAS exome AF: 0.805

Gnomad4 SAS exome AF: 0.829

Gnomad4 FIN exome AF: 0.918

Gnomad4 NFE exome AF: 0.896

Gnomad4 OTH exome AF: 0.885

GnomAD4 genome AF: 0.906 AC: 138043 AN: 152284 Hom.: 62801 Cov.: 32 AF XY: 0.906 AC XY: 67454 AN XY: 74456

Gnomad4 AFR AF: 0.976

Gnomad4 AMR AF: 0.869

Gnomad4 ASJ AF: 0.852

Gnomad4 EAS AF: 0.763

Gnomad4 SAS AF: 0.828

Gnomad4 FIN AF: 0.920

Gnomad4 NFE AF: 0.890

Gnomad4 OTH AF: 0.905

Alfa AF: 0.889 Hom.: 45422

Bravo AF: 0.908

TwinsUK AF: 0.909 AC: 3371

ALSPAC AF: 0.905 AC: 3486

ESP6500AA AF: 0.976 AC: 3576

ESP6500EA AF: 0.894 AC: 7299

ExAC AF: 0.874 AC: 105606

Asia WGS AF: 0.813 AC: 2828 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Benign	0.89
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.037	T
MetaRNN	Benign	0.0000026	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.074
Sift	Benign	0.16	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.072
MPC		0.10
ClinPred		0.0092	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs315675; hg19: chr4-25363901; COSMIC: COSV57181356;