1-227654338-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001367909.1(ZNF678):ā€‹c.88A>Gā€‹(p.Ile30Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000251 in 1,514,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000026 ( 0 hom. )

Consequence

ZNF678
NM_001367909.1 missense, splice_region

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.67
Variant links:
Genes affected
ZNF678 (HGNC:28652): (zinc finger protein 678) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.030741721).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF678NM_001367909.1 linkuse as main transcriptc.88A>G p.Ile30Val missense_variant, splice_region_variant 4/4 ENST00000343776.10 NP_001354838.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF678ENST00000343776.10 linkuse as main transcriptc.88A>G p.Ile30Val missense_variant, splice_region_variant 4/41 NM_001367909.1 ENSP00000344828 P1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152008
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000484
AC:
9
AN:
185952
Hom.:
0
AF XY:
0.0000597
AC XY:
6
AN XY:
100536
show subpopulations
Gnomad AFR exome
AF:
0.0000696
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000283
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000324
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000264
AC:
36
AN:
1362704
Hom.:
0
Cov.:
30
AF XY:
0.0000389
AC XY:
26
AN XY:
669122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000131
Gnomad4 SAS exome
AF:
0.000282
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000937
Gnomad4 OTH exome
AF:
0.0000179
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152008
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000578
AC:
7

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 GeneticsFeb 16, 2023The c.253A>G (p.I85V) alteration is located in exon 4 (coding exon 4) of the ZNF678 gene. This alteration results from a A to G substitution at nucleotide position 253, causing the isoleucine (I) at amino acid position 85 to be replaced by a valine (V). 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
0.088
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
0.22
DANN
Benign
0.48
DEOGEN2
Benign
0.0038
T;.;.;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.000010
N
LIST_S2
Benign
0.38
.;T;T;T
M_CAP
Benign
0.0017
T
MetaRNN
Benign
0.031
T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.030
N;.;.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.030
N;.;N;.
REVEL
Benign
0.0020
Sift
Benign
0.76
T;.;T;.
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.080
B;.;.;B
Vest4
0.021
MutPred
0.39
Loss of catalytic residue at I30 (P = 0.1509);Loss of catalytic residue at I30 (P = 0.1509);.;Loss of catalytic residue at I30 (P = 0.1509);
MVP
0.014
MPC
0.017
ClinPred
0.017
T
GERP RS
-3.3
Varity_R
0.022
gMVP
0.027

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: rs747539296; hg19: chr1-227842039; API