X-104114197-T-C

Position:

• chrX-104114197-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000594199.3(SLC25A53):​c.-31-8909A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC25A53 ENST00000594199.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

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]

ZCCHC18 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCCHC18	NM_001143978.3	c.86T>C	p.Leu29Pro	missense_variant	3/3	ENST00000650639.1	NP_001137450.1
SLC25A53	NM_001012755.5	c.-31-8909A>G		intron_variant		ENST00000594199.3	NP_001012773.2
ZCCHC18	XM_011531012.4	c.86T>C	p.Leu29Pro	missense_variant	3/3		XP_011529314.1
ZCCHC18	NR_026694.3	n.671+624T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCCHC18	ENST00000650639.1	c.86T>C	p.Leu29Pro	missense_variant	3/3		NM_001143978.3	ENSP00000498828.1
SLC25A53	ENST00000594199.3	c.-31-8909A>G		intron_variant		1	NM_001012755.5	ENSP00000468980.1
ZCCHC18	ENST00000537356.3	c.86T>C	p.Leu29Pro	missense_variant	2/2	5		ENSP00000473824.1
ZCCHC18	ENST00000422784.5	n.650+624T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

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

Apr 13, 2022

The c.86T>C (p.L29P) alteration is located in exon 3 (coding exon 1) of the ZCCHC18 gene. This alteration results from a T to C substitution at nucleotide position 86, causing the leucine (L) at amino acid position 29 to be replaced by a proline (P). 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	0.22
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.66
DEOGEN2	Benign	0.083	T;T
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.0027	T
MetaRNN	Uncertain	0.66	D;D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.74
MVP		0.061
MPC		0.88
GERP RS		1.7
Varity_R		0.46
gMVP		0.92

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

Other links and lift over

dbSNP: rs977240857; hg19: chrX-103358888;