18-35242669-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001135178.3(ZNF397):ā€‹c.199G>Cā€‹(p.Ala67Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

ZNF397
NM_001135178.3 missense

Scores

5
6
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67
Variant links:
Genes affected
ZNF397 (HGNC:18818): (zinc finger protein 397) This gene encodes a protein with a N-terminal SCAN domain, and the longer isoform contains nine C2H2-type zinc finger repeats in the C-terminal domain. The protein localizes to centromeres during interphase and early prophase, and different isoforms can repress or activate transcription in transfection studies. Multiple transcript variants encoding different isoforms have been found for this gene. Additional variants have been described, but their biological validity has not been determined. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF397NM_001135178.3 linkuse as main transcriptc.199G>C p.Ala67Pro missense_variant 2/4 ENST00000330501.12 NP_001128650.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF397ENST00000330501.12 linkuse as main transcriptc.199G>C p.Ala67Pro missense_variant 2/41 NM_001135178.3 ENSP00000331577 P1Q8NF99-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152236
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00000398
AC:
1
AN:
251376
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
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:
0.00000958
AC:
14
AN:
1461872
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
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:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152236
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
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:
0.0000227

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 GeneticsJun 04, 2024The c.199G>C (p.A67P) alteration is located in exon 2 (coding exon 1) of the ZNF397 gene. This alteration results from a G to C substitution at nucleotide position 199, causing the alanine (A) 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
Pathogenic
0.95
BayesDel_addAF
Benign
-0.0052
T
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T;.;T;.;.;.;T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.83
T;.;T;T;T;T;T
M_CAP
Benign
0.025
T
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D
MetaSVM
Benign
-0.61
T
MutationAssessor
Pathogenic
3.8
.;H;H;H;.;H;.
MutationTaster
Benign
0.94
D;D;D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-4.0
.;.;D;D;D;.;.
REVEL
Benign
0.22
Sift
Uncertain
0.0030
.;.;D;D;D;.;.
Sift4G
Uncertain
0.0090
D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;D;D;.
Vest4
0.39, 0.38, 0.70, 0.79, 0.39, 0.38
MutPred
0.83
Gain of glycosylation at A67 (P = 0.0106);Gain of glycosylation at A67 (P = 0.0106);Gain of glycosylation at A67 (P = 0.0106);Gain of glycosylation at A67 (P = 0.0106);Gain of glycosylation at A67 (P = 0.0106);Gain of glycosylation at A67 (P = 0.0106);Gain of glycosylation at A67 (P = 0.0106);
MVP
0.23
MPC
0.74
ClinPred
0.97
D
GERP RS
4.2
Varity_R
0.85
gMVP
0.54

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: rs1441585070; hg19: chr18-32822633; API