X-48060492-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001282201.2(ZNF630):​c.196C>A​(p.Pro66Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,204,623 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 3 hem., cov: 22)
Exomes 𝑓: 0.000033 ( 0 hom. 9 hem. )

Consequence

ZNF630
NM_001282201.2 missense

Scores

2
2
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.169
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06928292).
BS2
High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF630NM_001282201.2 linkuse as main transcriptc.196C>A p.Pro66Thr missense_variant 4/5 ENST00000276054.9 NP_001269130.1
ZNF630-AS1NR_046742.2 linkuse as main transcriptn.123+4060G>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF630ENST00000276054.9 linkuse as main transcriptc.196C>A p.Pro66Thr missense_variant 4/51 NM_001282201.2 ENSP00000354683 P1Q2M218-1
ZNF630-AS1ENST00000614448.1 linkuse as main transcriptn.123+4060G>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000633
AC:
7
AN:
110612
Hom.:
0
Cov.:
22
AF XY:
0.0000909
AC XY:
3
AN XY:
32998
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000675
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000117
AC:
21
AN:
178745
Hom.:
0
AF XY:
0.0000766
AC XY:
5
AN XY:
65239
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000705
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:
0.0000125
Gnomad OTH exome
AF:
0.000227
GnomAD4 exome
AF:
0.0000329
AC:
36
AN:
1094011
Hom.:
0
Cov.:
30
AF XY:
0.0000250
AC XY:
9
AN XY:
359621
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000743
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:
0.0000107
Gnomad4 OTH exome
AF:
0.0000218
GnomAD4 genome
AF:
0.0000633
AC:
7
AN:
110612
Hom.:
0
Cov.:
22
AF XY:
0.0000909
AC XY:
3
AN XY:
32998
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000675
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000121
ExAC
AF:
0.000108
AC:
13
EpiCase
AF:
0.0000549
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2021The c.196C>A (p.P66T) alteration is located in exon 4 (coding exon 3) of the ZNF630 gene. This alteration results from a C to A substitution at nucleotide position 196, causing the proline (P) at amino acid position 66 to be replaced by a threonine (T). 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
0.32
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
10
DANN
Benign
0.84
DEOGEN2
Benign
0.067
.;T;T;.;.
FATHMM_MKL
Benign
0.038
N
LIST_S2
Benign
0.14
T;T;.;T;T
M_CAP
Benign
0.0010
T
MetaRNN
Benign
0.069
T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Pathogenic
3.1
.;M;M;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Pathogenic
-6.0
.;.;D;.;D
REVEL
Benign
0.049
Sift
Uncertain
0.0030
.;.;D;.;D
Sift4G
Uncertain
0.011
D;D;D;.;.
Polyphen
0.022
.;B;B;.;.
Vest4
0.20
MutPred
0.48
.;Loss of methylation at K64 (P = 0.0839);Loss of methylation at K64 (P = 0.0839);.;Loss of methylation at K64 (P = 0.0839);
MVP
0.014
MPC
0.033
ClinPred
0.14
T
GERP RS
0.21
Varity_R
0.25
gMVP
0.099

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782466007; hg19: chrX-47919871; API