chr17-8121693-C-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_001165967.2(HES7):c.571G>T(p.Asp191Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,327,614 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 Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
HES7
NM_001165967.2 missense
NM_001165967.2 missense
Scores
2
4
13
Clinical Significance
Conservation
PhyloP100: 0.744
Genes affected
HES7 (HGNC:15977): (hes family bHLH transcription factor 7) This gene encodes a member of the hairy and enhancer of split family of bHLH transcription factors. The mouse ortholog of this gene is regulated by Notch signaling. The protein functions as a transcriptional repressor, and is implicated in correct patterning of the axial skeleton. A mutation in this gene has been shown to result in spondylocostal dysostosis. Multiple transcript variants 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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a chain Transcription factor HES-7 (size 224) in uniprot entity HES7_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001165967.2
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-8121693-C-A is Pathogenic according to our data. Variant chr17-8121693-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 30697.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.37008095). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HES7 | NM_001165967.2 | c.571G>T | p.Asp191Tyr | missense_variant | 4/4 | ENST00000541682.7 | |
HES7 | NM_032580.4 | c.556G>T | p.Asp186Tyr | missense_variant | 4/4 | ||
HES7 | XM_047436940.1 | c.667G>T | p.Asp223Tyr | missense_variant | 3/3 | ||
HES7 | XM_047436941.1 | c.658G>T | p.Asp220Tyr | missense_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HES7 | ENST00000541682.7 | c.571G>T | p.Asp191Tyr | missense_variant | 4/4 | 1 | NM_001165967.2 | A1 | |
HES7 | ENST00000317814.8 | c.556G>T | p.Asp186Tyr | missense_variant | 4/4 | 1 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152076Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000400 AC: 47AN: 1175538Hom.: 0 Cov.: 30 AF XY: 0.0000407 AC XY: 23AN XY: 565202
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Spondylocostal dysostosis 4, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2010 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N
MutationTaster
Benign
N;N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
0.036
.;B
Vest4
MutPred
0.26
.;Gain of phosphorylation at D186 (P = 0.0293);
MVP
MPC
ClinPred
T
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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