Genetic Variant HES7:p.Gly193Cys (chr17-8121687-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001165967.2(HES7):c.577G>T(p.Gly193Cys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HES7
NM_001165967.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00100

Publications

0 publications found

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]

HES7 Gene-Disease associations (from GenCC):

spondylocostal dysostosis 4, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal recessive spondylocostal dysostosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HES7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.76017 (below the threshold of 3.09). Trascript score misZ: -2.7124 (below the threshold of 3.09). GenCC associations: The gene is linked to spondylocostal dysostosis 4, autosomal recessive, autosomal recessive spondylocostal dysostosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.3630786).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165967.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES7	NM_001165967.2	MANE Select	c.577G>T	p.Gly193Cys	missense	Exon 4 of 4	NP_001159439.1	Q9BYE0-2
	HES7	NM_032580.4		c.562G>T	p.Gly188Cys	missense	Exon 4 of 4	NP_115969.2	Q9BYE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HES7	ENST00000541682.7	TSL:1 MANE Select	c.577G>T	p.Gly193Cys	missense	Exon 4 of 4	ENSP00000446205.2	Q9BYE0-2
HES7	ENST00000317814.8	TSL:1	c.562G>T	p.Gly188Cys	missense	Exon 4 of 4	ENSP00000314774.4	Q9BYE0-1
HES7	ENST00000577735.1	TSL:3	c.*117G>T		downstream_gene	N/A	ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

2892

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1174824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

564578

African (AFR)

AF:

0.00

AC:

AN:

23422

American (AMR)

AF:

0.00

AC:

AN:

8988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16146

East Asian (EAS)

AF:

0.00

AC:

AN:

26988

South Asian (SAS)

AF:

0.00

AC:

AN:

43382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

977054

Other (OTH)

AF:

0.00

AC:

AN:

48352

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0024

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.69

PhyloP100

-0.0010

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.33

Sift

Benign

0.12

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.25

MutPred

0.20

Loss of relative solvent accessibility (P = 0.0676)

MVP

0.79

MPC

1.9

ClinPred

0.85

GERP RS

3.1

Varity_R

0.20

gMVP

0.31

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over