17-8121681-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001165967.2(HES7):c.583C>A(p.Pro195Thr) 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 1,174,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. P195A) 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

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 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=0.16926983).

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.583C>A	p.Pro195Thr	missense	Exon 4 of 4	NP_001159439.1	Q9BYE0-2
	HES7	NM_032580.4		c.568C>A	p.Pro190Thr	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.583C>A	p.Pro195Thr	missense	Exon 4 of 4	ENSP00000446205.2	Q9BYE0-2
HES7	ENST00000317814.8	TSL:1	c.568C>A	p.Pro190Thr	missense	Exon 4 of 4	ENSP00000314774.4	Q9BYE0-1
HES7	ENST00000577735.1	TSL:3	c.*123C>A		downstream_gene	N/A	ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000170

AC:

AN:

1174104

Hom.:

Cov.:

AF XY:

0.00000177

AC XY:

AN XY:

564058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23410

American (AMR)

AF:

0.00

AC:

AN:

8962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16118

East Asian (EAS)

AF:

0.00

AC:

AN:

26962

South Asian (SAS)

AF:

0.00

AC:

AN:

43230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3270

European-Non Finnish (NFE)

AF:

0.00000205

AC:

AN:

976636

Other (OTH)

AF:

0.00

AC:

AN:

48320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.55

PhyloP100

1.6

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

REVEL

Benign

0.24

Sift

Benign

0.090

Sift4G

Benign

0.43

Polyphen

0.023

Vest4

0.033

MutPred

0.098

Gain of phosphorylation at P190 (P = 0.0243)

MVP

0.28

MPC

1.0

ClinPred

0.21

GERP RS

4.1

Varity_R

0.11

gMVP

0.30

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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