X-48059402-T-C

Variant names:

• chrX-48059402-T-C
• rs907281532
• NM_001282201.2:c.1040A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001282201.2(ZNF630):​c.1040A>G​(p.Tyr347Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,094,767 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: ZNF630 NM_001282201.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.134

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:41215): (ZNF630 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20220894).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF630	NM_001282201.2	c.1040A>G	p.Tyr347Cys	missense_variant	Exon 5 of 5	ENST00000276054.9	NP_001269130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF630	ENST00000276054.9	c.1040A>G	p.Tyr347Cys	missense_variant	Exon 5 of 5	1	NM_001282201.2	ENSP00000354683.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1094767 Hom.: 0 Cov.: 35 AF XY: 0.00000833 AC XY: 3 AN XY: 360339

Gnomad4 AFR exome AF: 0.0000381

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1040A>G (p.Y347C) alteration is located in exon 5 (coding exon 4) of the ZNF630 gene. This alteration results from a A to G substitution at nucleotide position 1040, causing the tyrosine (Y) at amino acid position 347 to be replaced by a cysteine (C). 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	0.29
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;T;T;.
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.22	T;T;.;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	.;M;M;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-8.1	.;.;D;D
REVEL	Benign	0.069
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.26	.;B;B;.
Vest4		0.23
MutPred		0.60		.;Gain of disorder (P = 0.048);Gain of disorder (P = 0.048);.;
MVP		0.26
MPC		0.22
ClinPred		0.96	D
GERP RS		1.1
Varity_R		0.61
gMVP		0.041

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: rs907281532; hg19: chrX-47918791;