X-104114796-C-T

Position:

• chrX-104114796-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001143978.3(ZCCHC18):​c.685C>T​(p.Arg229Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,035 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 3 hem.)
• Consequence: ZCCHC18 NM_001143978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.00

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]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034184247).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC18	NM_001143978.3	c.685C>T	p.Arg229Trp	missense_variant	3/3	ENST00000650639.1	NP_001137450.1
SLC25A53	NM_001012755.5	c.-31-9508G>A		intron_variant		ENST00000594199.3	NP_001012773.2
ZCCHC18	XM_011531012.4	c.685C>T	p.Arg229Trp	missense_variant	3/3		XP_011529314.1
ZCCHC18	NR_026694.3	n.672-456C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC18	ENST00000650639.1	c.685C>T	p.Arg229Trp	missense_variant	3/3		NM_001143978.3	ENSP00000498828	P1
SLC25A53	ENST00000594199.3	c.-31-9508G>A		intron_variant		1	NM_001012755.5	ENSP00000468980	P1
ZCCHC18	ENST00000537356.3	c.685C>T	p.Arg229Trp	missense_variant	2/2	5		ENSP00000473824	P1
ZCCHC18	ENST00000422784.5	n.651-456C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097035 Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 3 AN XY: 362421

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 23

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

Aug 16, 2022

The c.685C>T (p.R229W) alteration is located in exon 3 (coding exon 1) of the ZCCHC18 gene. This alteration results from a C to T substitution at nucleotide position 685, causing the arginine (R) at amino acid position 229 to be replaced by a tryptophan (W). 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	0.079
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.85
DEOGEN2	Benign	0.016	T;T
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.00098	T
MetaRNN	Benign	0.034	T;T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
Sift4G	Uncertain	0.025	D;D
Polyphen		0.0020	B;B
Vest4		0.17
MVP		0.048
MPC		0.18
GERP RS		-1.2
Varity_R		0.071
gMVP		0.42

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: rs2075368883; hg19: chrX-103359487; COSMIC: COSV62460961; COSMIC: COSV62460961;