chr17-8121693-C-A

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

Scores

2
4
13

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.744
Variant links:
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
HES7NM_001165967.2 linkuse as main transcriptc.571G>T p.Asp191Tyr missense_variant 4/4 ENST00000541682.7
HES7NM_032580.4 linkuse as main transcriptc.556G>T p.Asp186Tyr missense_variant 4/4
HES7XM_047436940.1 linkuse as main transcriptc.667G>T p.Asp223Tyr missense_variant 3/3
HES7XM_047436941.1 linkuse as main transcriptc.658G>T p.Asp220Tyr missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HES7ENST00000541682.7 linkuse as main transcriptc.571G>T p.Asp191Tyr missense_variant 4/41 NM_001165967.2 A1Q9BYE0-2
HES7ENST00000317814.8 linkuse as main transcriptc.556G>T p.Asp186Tyr missense_variant 4/41 P4Q9BYE0-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152076
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000400
AC:
47
AN:
1175538
Hom.:
0
Cov.:
30
AF XY:
0.0000407
AC XY:
23
AN XY:
565202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000185
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000419
Gnomad4 OTH exome
AF:
0.0000207
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152076
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

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 providedliterature onlyOMIMJun 01, 2010- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
21
DANN
Benign
0.85
DEOGEN2
Benign
0.19
.;T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.67
T;T
M_CAP
Pathogenic
0.78
D
MetaRNN
Benign
0.37
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.55
.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.54
N;N
REVEL
Uncertain
0.42
Sift
Benign
1.0
T;T
Sift4G
Uncertain
0.035
D;D
Polyphen
0.036
.;B
Vest4
0.73
MutPred
0.26
.;Gain of phosphorylation at D186 (P = 0.0293);
MVP
0.99
MPC
1.6
ClinPred
0.18
T
GERP RS
1.8
Varity_R
0.14
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387906978; hg19: chr17-8025011; API