10-37831910-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_021045.3(ZNF248):​c.1445A>G​(p.His482Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ZNF248
NM_021045.3 missense

Scores

13
2
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.02
Variant links:
Genes affected
ZNF248 (HGNC:13041): (zinc finger protein 248) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF248NM_021045.3 linkc.1445A>G p.His482Arg missense_variant 6/6 ENST00000395867.8 NP_066383.1 Q8NDW4-1A2RUI7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF248ENST00000395867.8 linkc.1445A>G p.His482Arg missense_variant 6/61 NM_021045.3 ENSP00000379208.3 Q8NDW4-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

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 15, 2023The c.1445A>G (p.H482R) alteration is located in exon 6 (coding exon 4) of the ZNF248 gene. This alteration results from a A to G substitution at nucleotide position 1445, causing the histidine (H) at amino acid position 482 to be replaced by an arginine (R). 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
0.98
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T;T
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.44
.;T
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
3.8
H;H
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.8
D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.73
MutPred
0.90
Gain of MoRF binding (P = 0.0287);Gain of MoRF binding (P = 0.0287);
MVP
0.93
MPC
0.59
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.89
gMVP
0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-38120838; API