chr17-8121668-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_001165967.2(HES7):​c.596C>T​(p.Thr199Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 1,329,562 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

HES7
NM_001165967.2 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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=0.3648708).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HES7NM_001165967.2 linkuse as main transcriptc.596C>T p.Thr199Ile missense_variant 4/4 ENST00000541682.7
HES7NM_032580.4 linkuse as main transcriptc.581C>T p.Thr194Ile missense_variant 4/4
HES7XM_047436940.1 linkuse as main transcriptc.692C>T p.Thr231Ile missense_variant 3/3
HES7XM_047436941.1 linkuse as main transcriptc.683C>T p.Thr228Ile missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HES7ENST00000541682.7 linkuse as main transcriptc.596C>T p.Thr199Ile missense_variant 4/41 NM_001165967.2 A1Q9BYE0-2
HES7ENST00000317814.8 linkuse as main transcriptc.581C>T p.Thr194Ile missense_variant 4/41 P4Q9BYE0-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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:
0.00000170
AC:
2
AN:
1177426
Hom.:
0
Cov.:
30
AF XY:
0.00000353
AC XY:
2
AN XY:
566126
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:
0.00
Gnomad4 OTH exome
AF:
0.0000412
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 18, 2024The c.581C>T (p.T194I) alteration is located in exon 4 (coding exon 4) of the HES7 gene. This alteration results from a C to T substitution at nucleotide position 581, causing the threonine (T) at amino acid position 194 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 30, 2021In 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with HES7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces threonine with isoleucine at codon 194 of the HES7 protein (p.Thr194Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.030
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
.;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.44
T;T
M_CAP
Pathogenic
0.95
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
0.69
.;N
MutationTaster
Benign
0.99
D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-1.4
N;N
REVEL
Benign
0.24
Sift
Benign
0.20
T;T
Sift4G
Benign
0.42
T;T
Polyphen
1.0
.;D
Vest4
0.22
MutPred
0.26
.;Loss of phosphorylation at T194 (P = 0.0059);
MVP
0.52
MPC
1.9
ClinPred
0.88
D
GERP RS
5.1
Varity_R
0.071
gMVP
0.58

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: rs1365151656; hg19: chr17-8024986; API