chr1-999365-C-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_021170.4(HES4):āc.360G>Cā(p.Glu120Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,498,446 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 0.00013 ( 0 hom., cov: 34)
Exomes š: 0.000092 ( 0 hom. )
Consequence
HES4
NM_021170.4 missense
NM_021170.4 missense
Scores
3
10
4
Clinical Significance
Conservation
PhyloP100: 0.804
Genes affected
HES4 (HGNC:24149): (hes family bHLH transcription factor 4) 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 anterior/posterior pattern specification and regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2678033).
BS2
High AC in GnomAd4 at 20 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HES4 | NM_021170.4 | c.360G>C | p.Glu120Asp | missense_variant | 4/4 | ENST00000304952.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HES4 | ENST00000304952.11 | c.360G>C | p.Glu120Asp | missense_variant | 4/4 | 1 | NM_021170.4 | P1 | |
HES4 | ENST00000428771.6 | c.438G>C | p.Glu146Asp | missense_variant | 3/3 | 2 | |||
HES4 | ENST00000484667.2 | c.264G>C | p.Glu88Asp | missense_variant | 3/3 | 3 | |||
HES4 | ENST00000481869.1 | n.639G>C | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152176Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000148 AC: 17AN: 114836Hom.: 0 AF XY: 0.0000904 AC XY: 6AN XY: 66382
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GnomAD4 exome AF: 0.0000921 AC: 124AN: 1346162Hom.: 0 Cov.: 30 AF XY: 0.0000887 AC XY: 59AN XY: 665194
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GnomAD4 genome AF: 0.000131 AC: 20AN: 152284Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12AN XY: 74454
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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 | Jul 13, 2022 | The c.438G>C (p.E146D) alteration is located in exon 3 (coding exon 3) of the HES4 gene. This alteration results from a G to C substitution at nucleotide position 438, causing the glutamic acid (E) at amino acid position 146 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
P;D;.
Vest4
MutPred
Gain of helix (P = 0.0854);.;.;
MVP
MPC
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