X-48058702-G-C

Position:

• chrX-48058702-G-C

Variant summary

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

The NM_001282201.2(ZNF630):​c.1740C>G​(p.Phe580Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,094,338 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: ZNF630 NM_001282201.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.510

Genes affected

ZNF630 (HGNC:28855): (zinc finger protein 630) This gene encodes a protein containing an N-terminal Kruppel-associated box-containing (KRAB) domain and 13 Kruppel-type C2H2 zinc finger domains. This gene resides on an area of chromosome X that has been implicated in nonsyndromic X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ZNF630-AS1 (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
ZNF630	NM_001282201.2	c.1740C>G	p.Phe580Leu	missense_variant	5/5	ENST00000276054.9	NP_001269130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF630	ENST00000276054.9	c.1740C>G	p.Phe580Leu	missense_variant	5/5	1	NM_001282201.2	ENSP00000354683.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1094338 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 1 AN XY: 359860

Gnomad4 AFR exome AF: 0.00

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: 0.00000238

Gnomad4 OTH exome AF: 0.0000218

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

Oct 19, 2024

The c.1740C>G (p.F580L) alteration is located in exon 5 (coding exon 4) of the ZNF630 gene. This alteration results from a C to G substitution at nucleotide position 1740, causing the phenylalanine (F) at amino acid position 580 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T;.
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.69	T;T;.;T
M_CAP	Benign	0.0034	T
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	.;M;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	.;.;D;D
REVEL	Benign	0.13
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Uncertain	0.052	T;D;D;D
Polyphen		0.82	.;P;P;.
Vest4		0.33
MutPred		0.79		.;Loss of methylation at K583 (P = 0.1014);Loss of methylation at K583 (P = 0.1014);.;
MVP		0.10
MPC		0.029
ClinPred		0.94	D
GERP RS		1.4
Varity_R		0.78
gMVP		0.047

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-47918091;