chr17-8121687-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001165967.2(HES7):​c.577G>A​(p.Gly193Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,174,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G193D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

HES7
NM_001165967.2 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00100
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 2 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;
BP4
Computational evidence support a benign effect (MetaRNN=0.18055972).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HES7NM_001165967.2 linkuse as main transcriptc.577G>A p.Gly193Ser missense_variant 4/4 ENST00000541682.7
HES7NM_032580.4 linkuse as main transcriptc.562G>A p.Gly188Ser missense_variant 4/4
HES7XM_047436940.1 linkuse as main transcriptc.673G>A p.Gly225Ser missense_variant 3/3
HES7XM_047436941.1 linkuse as main transcriptc.664G>A p.Gly222Ser missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HES7ENST00000541682.7 linkuse as main transcriptc.577G>A p.Gly193Ser missense_variant 4/41 NM_001165967.2 A1Q9BYE0-2
HES7ENST00000317814.8 linkuse as main transcriptc.562G>A p.Gly188Ser missense_variant 4/41 P4Q9BYE0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000170
AC:
2
AN:
1174824
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
564578
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000205
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 30, 2024The c.562G>A (p.G188S) alteration is located in exon 4 (coding exon 4) of the HES7 gene. This alteration results from a G to A substitution at nucleotide position 562, causing the glycine (G) at amino acid position 188 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
.;T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.61
T;T
M_CAP
Pathogenic
0.77
D
MetaRNN
Benign
0.18
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.69
.;N
MutationTaster
Benign
0.98
N;N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-0.33
N;N
REVEL
Benign
0.19
Sift
Benign
0.75
T;T
Sift4G
Benign
0.46
T;T
Polyphen
0.23
.;B
Vest4
0.073
MutPred
0.21
.;Gain of glycosylation at G188 (P = 0.013);
MVP
0.67
MPC
1.8
ClinPred
0.47
T
GERP RS
3.1
Varity_R
0.062
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-8025005; API