rs387906978

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PP2PP5BP4

The NM_001165967.2(HES7):c.571G>T(p.Asp191Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,327,614 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 Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

HES7
NM_001165967.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.744

Publications

7 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 5 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;

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.

PP5

Variant 17-8121693-C-A is Pathogenic according to our data. Variant chr17-8121693-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 30697.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.37008095). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES7	NM_001165967.2 link	c.571G>T	p.Asp191Tyr	missense_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1	Q9BYE0-2
HES7	NM_032580.4 link	c.556G>T	p.Asp186Tyr	missense_variant	Exon 4 of 4		NP_115969.2	Q9BYE0-1
HES7	XM_047436940.1 link	c.667G>T	p.Asp223Tyr	missense_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1 link	c.658G>T	p.Asp220Tyr	missense_variant	Exon 5 of 5		XP_047292897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HES7	ENST00000541682.7 link	c.571G>T	p.Asp191Tyr	missense_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2	Q9BYE0-2
HES7	ENST00000317814.8 link	c.556G>T	p.Asp186Tyr	missense_variant	Exon 4 of 4	1		ENSP00000314774.4	Q9BYE0-1
HES7	ENST00000577735.1 link	c.*111G>T		downstream_gene_variant		3		ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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:

0.0000400

AC:

AN:

1175538

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

565202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23442

American (AMR)

AF:

0.00

AC:

AN:

9068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16144

East Asian (EAS)

AF:

0.000185

AC:

AN:

27024

South Asian (SAS)

AF:

0.00

AC:

AN:

43536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3284

European-Non Finnish (NFE)

AF:

0.0000419

AC:

AN:

977512

Other (OTH)

AF:

0.0000207

AC:

AN:

48342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 4, autosomal recessive

Pathogenic:1

Jun 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.19

.;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.55

.;N

PhyloP100

0.74

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.54

N;N

REVEL

Uncertain

0.42

Sift

Benign

1.0

T;T

Sift4G

Uncertain

0.035

D;D

Polyphen

0.036

.;B

Vest4

0.73

MutPred

0.26

.;Gain of phosphorylation at D186 (P = 0.0293);

MVP

0.99

MPC

1.6

ClinPred

0.18

GERP RS

1.8

Varity_R

0.14

gMVP

0.55

Mutation Taster

=14/86

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over