chr16-72787693-G-C
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_006885.4(ZFHX3):āc.10583C>Gā(p.Ser3528Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000598 in 1,438,636 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 (ā ).
Frequency
Genomes: š 0.000068 ( 0 hom., cov: 31)
Exomes š: 0.000059 ( 0 hom. )
Consequence
ZFHX3
NM_006885.4 missense
NM_006885.4 missense
Scores
10
8
Clinical Significance
Conservation
PhyloP100: 4.19
Genes affected
ZFHX3 (HGNC:777): (zinc finger homeobox 3) This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. Multiple transcript variants expressed from alternate promoters and encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
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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=0.21607322).
BS2
High AC in GnomAd4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZFHX3 | NM_006885.4 | c.10583C>G | p.Ser3528Trp | missense_variant | 10/10 | ENST00000268489.10 | |
ZFHX3-AS1 | NR_171702.1 | n.391-33080G>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZFHX3 | ENST00000268489.10 | c.10583C>G | p.Ser3528Trp | missense_variant | 10/10 | 1 | NM_006885.4 | P1 | |
ZFHX3-AS1 | ENST00000687589.1 | n.482+5874G>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000684 AC: 10AN: 146116Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000861 AC: 15AN: 174288Hom.: 0 AF XY: 0.000103 AC XY: 10AN XY: 97304
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GnomAD4 exome AF: 0.0000588 AC: 76AN: 1292520Hom.: 0 Cov.: 36 AF XY: 0.0000676 AC XY: 43AN XY: 635682
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GnomAD4 genome AF: 0.0000684 AC: 10AN: 146116Hom.: 0 Cov.: 31 AF XY: 0.0000846 AC XY: 6AN XY: 70908
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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 | Apr 25, 2022 | The c.10583C>G (p.S3528W) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a C to G substitution at nucleotide position 10583, causing the serine (S) at amino acid position 3528 to be replaced by a tryptophan (W). 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
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
P;.;P
Vest4
MutPred
Loss of disorder (P = 0.0071);.;Loss of disorder (P = 0.0071);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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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