X-57592248-G-C

Variant names:

• chrX-57592248-G-C
• rs758842956
• NM_007157.4:c.200G>C

Variant summary

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

The NM_007157.4(ZXDB):​c.200G>C​(p.Arg67Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 1,045,413 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000067 (0 hom. 1 hem.)
• Consequence: ZXDB NM_007157.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.243

Genes affected

ZXDB (HGNC:13199): (zinc finger X-linked duplicated B) The ZXDB gene is one of a pair of duplicated zinc finger genes on chromosome Xp11.21 (Greig et al., 1993 [PubMed 8268913]); see also ZXDA (MIM 300235).[supplied by OMIM, Jul 2010]

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=0.036958218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZXDB	NM_007157.4	c.200G>C	p.Arg67Pro	missense_variant	Exon 1 of 1	ENST00000374888.3	NP_009088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZXDB	ENST00000374888.3	c.200G>C	p.Arg67Pro	missense_variant	Exon 1 of 1	6	NM_007157.4	ENSP00000364023.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000202 AC: 2 AN: 99236 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 26226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000103

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: 0.00

GnomAD4 exome AF: 0.00000670 AC: 7 AN: 1045413 Hom.: 0 Cov.: 31 AF XY: 0.00000296 AC XY: 1 AN XY: 338193

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000681

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: 0.00000608

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.00000920 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.200G>C (p.R67P) alteration is located in exon 1 (coding exon 1) of the ZXDB gene. This alteration results from a G to C substitution at nucleotide position 200, causing the arginine (R) at amino acid position 67 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	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	12
DANN	Benign	0.38
DEOGEN2	Benign	0.0032	T
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.12	N
REVEL	Benign	0.0040
Sift	Benign	0.34	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.19		Loss of methylation at R67 (P = 0.0144);
MVP		0.068
MPC		1.5
ClinPred		0.043	T
GERP RS		-3.9
Varity_R		0.20
gMVP		0.15

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: rs758842956; hg19: chrX-57618681;