14-23522141-G-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_033400.3(ZFHX2):c.7540C>A(p.Leu2514Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000729 in 1,371,236 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: not found (cov: 33)
Exomes 𝑓: 7.3e-7 ( 0 hom. )
Consequence
ZFHX2
NM_033400.3 missense
NM_033400.3 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 6.71
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)
THTPA (HGNC:18987): (thiamine triphosphatase) This gene encodes an enzyme which catalyzes the biosynthesis of thiamine disphophate (vitamin B1) by hydrolysis of thiamine triphosphate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.39319736).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZFHX2 | NM_033400.3 | c.7540C>A | p.Leu2514Met | 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.7540C>A | p.Leu2514Met | missense_variant | 10/10 | 5 | NM_033400.3 | ENSP00000413418 | P1 | |
ZFHX2-AS1 | ENST00000553985.1 | n.238+7725G>T | intron_variant, non_coding_transcript_variant | 2 | ||||||
ZFHX2-AS1 | ENST00000554403.1 | n.1068+7725G>T | intron_variant, non_coding_transcript_variant | 2 | ||||||
ZFHX2-AS1 | ENST00000556354.5 | n.465+7725G>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.29e-7 AC: 1AN: 1371236Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 675776
GnomAD4 exome
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1
AN:
1371236
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Cov.:
36
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AC XY:
0
AN XY:
675776
Gnomad4 AFR exome
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GnomAD4 genome 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 submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The c.7540C>A (p.L2514M) alteration is located in exon 10 (coding exon 9) of the ZFHX2 gene. This alteration results from a C to A substitution at nucleotide position 7540, causing the leucine (L) at amino acid position 2514 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at H2513 (P = 0.0135);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at