chr17-8121681-G-C

Variant summary

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

The NM_001165967.2(HES7):​c.583C>G​(p.Pro195Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HES7
NM_001165967.2 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55
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=0.17651224).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HES7NM_001165967.2 linkuse as main transcriptc.583C>G p.Pro195Ala missense_variant 4/4 ENST00000541682.7
HES7NM_032580.4 linkuse as main transcriptc.568C>G p.Pro190Ala missense_variant 4/4
HES7XM_047436940.1 linkuse as main transcriptc.679C>G p.Pro227Ala missense_variant 3/3
HES7XM_047436941.1 linkuse as main transcriptc.670C>G p.Pro224Ala missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HES7ENST00000541682.7 linkuse as main transcriptc.583C>G p.Pro195Ala missense_variant 4/41 NM_001165967.2 A1Q9BYE0-2
HES7ENST00000317814.8 linkuse as main transcriptc.568C>G p.Pro190Ala missense_variant 4/41 P4Q9BYE0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 25, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with HES7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 190 of the HES7 protein (p.Pro190Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Benign
-0.058
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
.;T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.55
T;T
M_CAP
Pathogenic
0.60
D
MetaRNN
Benign
0.18
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.55
.;N
MutationTaster
Benign
0.94
N;N
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.21
Sift
Benign
0.097
T;T
Sift4G
Benign
0.44
T;T
Polyphen
0.010
.;B
Vest4
0.17
MutPred
0.12
.;Loss of glycosylation at P190 (P = 0.0568);
MVP
0.37
MPC
0.82
ClinPred
0.12
T
GERP RS
4.1
Varity_R
0.083
gMVP
0.24

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: rs1010298012; hg19: chr17-8024999; API