17-8121673-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001165967.2(HES7):​c.591C>T​(p.Pro197=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,327,368 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00094 ( 5 hom. )

Consequence

HES7
NM_001165967.2 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.781
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 Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
Variant 17-8121673-G-A is Benign according to our data. Variant chr17-8121673-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288808.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BP7
Synonymous conserved (PhyloP=0.781 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00329 (501/152190) while in subpopulation AFR AF= 0.00773 (321/41544). AF 95% confidence interval is 0.00703. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HES7NM_001165967.2 linkuse as main transcriptc.591C>T p.Pro197= synonymous_variant 4/4 ENST00000541682.7
HES7NM_032580.4 linkuse as main transcriptc.576C>T p.Pro192= synonymous_variant 4/4
HES7XM_047436940.1 linkuse as main transcriptc.687C>T p.Pro229= synonymous_variant 3/3
HES7XM_047436941.1 linkuse as main transcriptc.678C>T p.Pro226= synonymous_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HES7ENST00000541682.7 linkuse as main transcriptc.591C>T p.Pro197= synonymous_variant 4/41 NM_001165967.2 A1Q9BYE0-2
HES7ENST00000317814.8 linkuse as main transcriptc.576C>T p.Pro192= synonymous_variant 4/41 P4Q9BYE0-1

Frequencies

GnomAD3 genomes
AF:
0.00329
AC:
501
AN:
152082
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00775
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00589
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0159
Gnomad NFE
AF:
0.000897
Gnomad OTH
AF:
0.00670
GnomAD3 exomes
AF:
0.000693
AC:
1
AN:
1444
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
798
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00117
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000939
AC:
1104
AN:
1175178
Hom.:
5
Cov.:
30
AF XY:
0.000910
AC XY:
514
AN XY:
564664
show subpopulations
Gnomad4 AFR exome
AF:
0.00821
Gnomad4 AMR exome
AF:
0.00613
Gnomad4 ASJ exome
AF:
0.00298
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.0000367
Gnomad4 NFE exome
AF:
0.000651
Gnomad4 OTH exome
AF:
0.00273
GnomAD4 genome
AF:
0.00329
AC:
501
AN:
152190
Hom.:
3
Cov.:
32
AF XY:
0.00325
AC XY:
242
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.00773
Gnomad4 AMR
AF:
0.00588
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000897
Gnomad4 OTH
AF:
0.00663
Alfa
AF:
0.00228
Hom.:
1
Bravo
AF:
0.00476
Asia WGS
AF:
0.000871
AC:
3
AN:
3460

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 28, 2016- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 26, 2024- -
HES7-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 11, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Benign
11
DANN
Benign
0.96

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: rs558811781; hg19: chr17-8024991; API