Variant X-104114240-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001143978.3(ZCCHC18):c.129A>C(p.Arg43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,095,779 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

ZCCHC18
NM_001143978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

ZCCHC18 (HGNC:32459): (zinc finger CCHC-type containing 18) Predicted to enable metal ion binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC18 links:

SLC25A53 (HGNC:31894): (solute carrier family 25 member 53) Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC25A53 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12556654).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZCCHC18	NM_001143978.3 linkuse as main transcript	c.129A>C	p.Arg43Ser	missense_variant	3/3	ENST00000650639.1	NP_001137450.1
SLC25A53	NM_001012755.5 linkuse as main transcript	c.-31-8952T>G		intron_variant		ENST00000594199.3	NP_001012773.2
ZCCHC18	XM_011531012.4 linkuse as main transcript	c.129A>C	p.Arg43Ser	missense_variant	3/3		XP_011529314.1
ZCCHC18	NR_026694.3 linkuse as main transcript	n.671+667A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZCCHC18	ENST00000650639.1 linkuse as main transcript	c.129A>C	p.Arg43Ser	missense_variant	3/3		NM_001143978.3	ENSP00000498828	P1
SLC25A53	ENST00000594199.3 linkuse as main transcript	c.-31-8952T>G		intron_variant		1	NM_001012755.5	ENSP00000468980	P1
ZCCHC18	ENST00000537356.3 linkuse as main transcript	c.129A>C	p.Arg43Ser	missense_variant	2/2	5		ENSP00000473824	P1
ZCCHC18	ENST00000422784.5 linkuse as main transcript	n.650+667A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000173

AC:

AN:

173593

Hom.:

AF XY:

0.0000167

AC XY:

AN XY:

59867

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000226

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1095779

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

361351

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000133

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

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 31, 2024

The c.129A>C (p.R43S) alteration is located in exon 3 (coding exon 1) of the ZCCHC18 gene. This alteration results from a A to C substitution at nucleotide position 129, causing the arginine (R) at amino acid position 43 to be replaced by a serine (S). 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

0.23

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.078

T;T

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.74

.;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.13

T;T

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.72

P;P

Vest4

0.36

MVP

0.40

MPC

0.49

GERP RS

1.2

Varity_R

0.42

gMVP

0.59

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

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