Variant 4-25333946-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024936.3(ZCCHC4):c.644A>C(p.Lys215Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,606,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ZCCHC4
NM_024936.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

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]

ZCCHC4 links:

ZCCHC4 (HGNC:):

ZCCHC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.027304918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC4	NM_024936.3 linkuse as main transcript	c.644A>C	p.Lys215Thr	missense_variant	5/13	ENST00000302874.9	NP_079212.2	Q9H5U6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZCCHC4	ENST00000302874.9 linkuse as main transcript	c.644A>C	p.Lys215Thr	missense_variant	5/13	1	NM_024936.3	ENSP00000303468.4	Q9H5U6-1
ZCCHC4	ENST00000505451.5 linkuse as main transcript	n.669A>C		non_coding_transcript_exon_variant	5/9	1
ZCCHC4	ENST00000507760.5 linkuse as main transcript	n.644A>C		non_coding_transcript_exon_variant	5/9	1		ENSP00000422115.1	Q9H5U6-2
ZCCHC4	ENST00000505412.1 linkuse as main transcript	c.236A>C	p.Lys79Thr	missense_variant	2/10	3		ENSP00000422269.1	H0Y8V8

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000207

AC:

AN:

242052

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

131412

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000950

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.00000619

AC:

AN:

1453906

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000144

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000984

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000223

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.644A>C (p.K215T) alteration is located in exon 5 (coding exon 5) of the ZCCHC4 gene. This alteration results from a A to C substitution at nucleotide position 644, causing the lysine (K) at amino acid position 215 to be replaced by a threonine (T). 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

0.087

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.59

M_CAP

Benign

0.0064

MetaRNN

Benign

0.027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.63

REVEL

Benign

0.029

Sift

Benign

0.40

Sift4G

Benign

0.49

Polyphen

0.0

Vest4

0.23

MutPred

0.32

Gain of catalytic residue at D214 (P = 0.0123);

MVP

0.40

MPC

0.10

ClinPred

0.025

GERP RS

1.2

Varity_R

0.21

gMVP

0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over