rs768201846

Variant names:

• chrX-57592270-G-C
• rs768201846
• NM_007157.4:c.222G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-57592270-G-C
• chrX-57592270-G-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_007157.4(ZXDB):​c.222G>C​(p.Leu74Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000568 in 1,172,386 control chromosomes in the GnomAD database, including 2 homozygotes. There are 294 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00058 (2 hom. 285 hem.)
• Consequence: ZXDB NM_007157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.17
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0711042).
• BP6: Variant X-57592270-G-C is Benign according to our data. Variant chrX-57592270-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2345194.
• BS2: High Hemizygotes in GnomAd4 at 9 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZXDB	NM_007157.4	MANE Select	c.222G>C	p.Leu74Phe	missense	Exon 1 of 1	NP_009088.1	P98169

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZXDB	ENST00000374888.3	TSL:6 MANE Select	c.222G>C	p.Leu74Phe	missense	Exon 1 of 1	ENSP00000364023.1	P98169

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 53 AN: 110439 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000570

Gnomad ASJ AF: 0.000386

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000744

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00441

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000372 AC: 45 AN: 120835 AF XY: 0.000386

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000172

Gnomad EAS exome AF: 0.000115

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.000392

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000577 AC: 613 AN: 1061904 Hom.: 2 Cov.: 31 AF XY: 0.000824 AC XY: 285 AN XY: 346036

African (AFR) AF: 0.000645 AC: 15 AN: 23244

American (AMR) AF: 0.000245 AC: 8 AN: 32630

Ashkenazi Jewish (ASJ) AF: 0.00258 AC: 47 AN: 18239

East Asian (EAS) AF: 0.000222 AC: 6 AN: 27005

South Asian (SAS) AF: 0.00149 AC: 76 AN: 51024

European-Finnish (FIN) AF: 0.000210 AC: 7 AN: 33271

Middle Eastern (MID) AF: 0.000713 AC: 2 AN: 2807

European-Non Finnish (NFE) AF: 0.000514 AC: 426 AN: 829191

Other (OTH) AF: 0.000584 AC: 26 AN: 44493

GnomAD4 genome AF: 0.000480 AC: 53 AN: 110482 Hom.: 0 Cov.: 23 AF XY: 0.000269 AC XY: 9 AN XY: 33442

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000525 AC: 16 AN: 30465

American (AMR) AF: 0.000569 AC: 6 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.000386 AC: 1 AN: 2588

East Asian (EAS) AF: 0.00 AC: 0 AN: 3417

South Asian (SAS) AF: 0.000746 AC: 2 AN: 2680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6003

Middle Eastern (MID) AF: 0.00481 AC: 1 AN: 208

European-Non Finnish (NFE) AF: 0.000515 AC: 27 AN: 52420

Other (OTH) AF: 0.00 AC: 0 AN: 1498

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000277834), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000369 Hom.: 3

ExAC AF: 0.000529 AC: 59

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.079
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.97	D
Vest4		0.021
MutPred		0.17		Gain of glycosylation at S72 (P = 0.1381)
MVP		0.26
MPC		1.6
ClinPred		0.029	T
GERP RS		2.4
PromoterAI		-0.0086	Neutral
Varity_R		0.091
gMVP		0.041
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs768201846; hg19: chrX-57618703; COSMIC: COSV66492865;