chr14-23522138-G-A
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_033400.3(ZFHX2):c.7543C>T(p.Arg2515Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,524,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000082 ( 0 hom. )
Consequence
ZFHX2
NM_033400.3 missense
NM_033400.3 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 0.615
Genes affected
ZFHX2 (HGNC:20152): (zinc finger homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in regulation of sensory perception of pain. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
ZFHX2-AS1 (HGNC:52658): (ZFHX2 antisense RNA 1)
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.20289806).
BS2
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZFHX2 | NM_033400.3 | c.7543C>T | p.Arg2515Cys | missense_variant | 10/10 | ENST00000419474.5 | NP_207646.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZFHX2 | ENST00000419474.5 | c.7543C>T | p.Arg2515Cys | missense_variant | 10/10 | 5 | NM_033400.3 | ENSP00000413418 | P1 | |
ZFHX2-AS1 | ENST00000553985.1 | n.238+7722G>A | intron_variant, non_coding_transcript_variant | 2 | ||||||
ZFHX2-AS1 | ENST00000554403.1 | n.1068+7722G>A | intron_variant, non_coding_transcript_variant | 2 | ||||||
ZFHX2-AS1 | ENST00000556354.5 | n.465+7722G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152240Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000988 AC: 12AN: 121484Hom.: 0 AF XY: 0.000122 AC XY: 8AN XY: 65534
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GnomAD4 exome AF: 0.0000824 AC: 113AN: 1372136Hom.: 0 Cov.: 36 AF XY: 0.0000828 AC XY: 56AN XY: 676242
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GnomAD4 genome AF: 0.0000722 AC: 11AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74498
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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 submitter | clinical testing | Ambry Genetics | Feb 16, 2023 | The c.7543C>T (p.R2515C) alteration is located in exon 10 (coding exon 9) of the ZFHX2 gene. This alteration results from a C to T substitution at nucleotide position 7543, causing the arginine (R) at amino acid position 2515 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at H2513 (P = 0.0012);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at