X-104114544-G-T

Position:

• chrX-104114544-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001143978.3(ZCCHC18):​c.433G>T​(p.Ala145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 22)
• Consequence: ZCCHC18 NM_001143978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.431

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 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=0.04374087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC18	NM_001143978.3	c.433G>T	p.Ala145Ser	missense_variant	3/3	ENST00000650639.1	NP_001137450.1
SLC25A53	NM_001012755.5	c.-31-9256C>A		intron_variant		ENST00000594199.3	NP_001012773.2
ZCCHC18	XM_011531012.4	c.433G>T	p.Ala145Ser	missense_variant	3/3		XP_011529314.1
ZCCHC18	NR_026694.3	n.672-708G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC18	ENST00000650639.1	c.433G>T	p.Ala145Ser	missense_variant	3/3		NM_001143978.3	ENSP00000498828	P1
SLC25A53	ENST00000594199.3	c.-31-9256C>A		intron_variant		1	NM_001012755.5	ENSP00000468980	P1
ZCCHC18	ENST00000537356.3	c.433G>T	p.Ala145Ser	missense_variant	2/2	5		ENSP00000473824	P1
ZCCHC18	ENST00000422784.5	n.651-708G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

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

Dec 06, 2022

The c.433G>T (p.A145S) alteration is located in exon 3 (coding exon 1) of the ZCCHC18 gene. This alteration results from a G to T substitution at nucleotide position 433, causing the alanine (A) at amino acid position 145 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	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.3
DANN	Benign	0.73
DEOGEN2	Benign	0.013	T;T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.00076	T
MetaRNN	Benign	0.044	T;T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	0.86	N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.25	T;T
Polyphen		0.12	B;B
Vest4		0.23
MVP		0.29
MPC		0.31
GERP RS		-4.5
Varity_R		0.055
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-103359235;