16-31076784-C-G

Variant summary

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

The NM_014699.4(ZNF646):ā€‹c.460C>Gā€‹(p.Pro154Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

ZNF646
NM_014699.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0330
Variant links:
Genes affected
ZNF646 (HGNC:29004): (zinc finger protein 646) 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=0.038404226).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF646NM_014699.4 linkuse as main transcriptc.460C>G p.Pro154Ala missense_variant 2/3 ENST00000300850.5 NP_055514.3 O15015-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF646ENST00000300850.5 linkuse as main transcriptc.460C>G p.Pro154Ala missense_variant 2/31 NM_014699.4 ENSP00000300850.5 O15015-2
ZNF646ENST00000394979.2 linkuse as main transcriptc.460C>G p.Pro154Ala missense_variant 1/16 ENSP00000378429.2 O15015-1
ZNF646ENST00000428260.1 linkuse as main transcriptc.460C>G p.Pro154Ala missense_variant 2/23 ENSP00000391271.1 C9J3L0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251286
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000173
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:
0.00000547
AC:
8
AN:
1461686
Hom.:
0
Cov.:
29
AF XY:
0.00000688
AC XY:
5
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

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 GeneticsNov 09, 2024The c.460C>G (p.P154A) alteration is located in exon 2 (coding exon 1) of the ZNF646 gene. This alteration results from a C to G substitution at nucleotide position 460, causing the proline (P) at amino acid position 154 to be replaced by an alanine (A). 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
0.059
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
5.3
DANN
Benign
0.68
DEOGEN2
Benign
0.015
.;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.63
T;T;T
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.038
T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.2
L;.;L
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.91
N;N;N
REVEL
Benign
0.013
Sift
Benign
0.75
T;T;T
Sift4G
Benign
0.73
T;T;T
Polyphen
0.0080
B;.;.
Vest4
0.087
MutPred
0.40
Loss of stability (P = 0.2662);Loss of stability (P = 0.2662);Loss of stability (P = 0.2662);
MVP
0.16
MPC
0.21
ClinPred
0.028
T
GERP RS
2.9
Varity_R
0.027
gMVP
0.37

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: rs754626534; hg19: chr16-31088105; API