rs315675

Variant names:

• chr4-25362279-T-A
• rs315675
• NM_024936.3:c.1187T>A

Variant summary

Our verdict is Benign. The variant received -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. 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: 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
• Publications: 31 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
ZCCHC4	NM_024936.3	c.1187T>A	p.Leu396His	missense_variant	Exon 10 of 13	ENST00000302874.9	NP_079212.2
ZCCHC4	XM_011513835.3	c.1232T>A	p.Leu411His	missense_variant	Exon 11 of 14		XP_011512137.1
ZCCHC4	XM_017008129.3	c.935T>A	p.Leu312His	missense_variant	Exon 8 of 11		XP_016863618.1
ZCCHC4	XR_925324.4	n.1268T>A		non_coding_transcript_exon_variant	Exon 11 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZCCHC4	ENST00000302874.9	c.1187T>A	p.Leu396His	missense_variant	Exon 10 of 13	1	NM_024936.3	ENSP00000303468.4

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

GnomAD2 exomes AF: 0.873 AC: 216607 AN: 248096 AF XY: 0.871

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 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

African (AFR) AF: 0.983 AC: 32756 AN: 33332

American (AMR) AF: 0.841 AC: 37282 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 22301 AN: 25994

East Asian (EAS) AF: 0.805 AC: 31846 AN: 39584

South Asian (SAS) AF: 0.829 AC: 70288 AN: 84762

European-Finnish (FIN) AF: 0.918 AC: 48658 AN: 53014

Middle Eastern (MID) AF: 0.868 AC: 4987 AN: 5744

European-Non Finnish (NFE) AF: 0.896 AC: 992122 AN: 1107454

Other (OTH) AF: 0.885 AC: 53175 AN: 60078

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

African (AFR) AF: 0.976 AC: 40569 AN: 41558

American (AMR) AF: 0.869 AC: 13301 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 2957 AN: 3470

East Asian (EAS) AF: 0.763 AC: 3956 AN: 5184

South Asian (SAS) AF: 0.828 AC: 3989 AN: 4820

European-Finnish (FIN) AF: 0.920 AC: 9760 AN: 10608

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.890 AC: 60538 AN: 68020

Other (OTH) AF: 0.905 AC: 1911 AN: 2112

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
PhyloP100		1.9
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
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

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