rs387906978

Positions:

chr17-8121693-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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;

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/exons	MANE
HES7	NM_001165967.2 linkuse as main transcript	c.571G>T	p.Asp191Tyr	missense_variant	4/4	ENST00000541682.7
HES7	NM_032580.4 linkuse as main transcript	c.556G>T	p.Asp186Tyr	missense_variant	4/4
HES7	XM_047436940.1 linkuse as main transcript	c.667G>T	p.Asp223Tyr	missense_variant	3/3
HES7	XM_047436941.1 linkuse as main transcript	c.658G>T	p.Asp220Tyr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HES7	ENST00000541682.7 linkuse as main transcript	c.571G>T	p.Asp191Tyr	missense_variant	4/4	1	NM_001165967.2	A1	Q9BYE0-2
HES7	ENST00000317814.8 linkuse as main transcript	c.556G>T	p.Asp186Tyr	missense_variant	4/4	1		P4	Q9BYE0-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000185

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000419

Gnomad4 OTH exome

AF:

0.0000207

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2010

- -

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

DANN

Benign

0.85

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

MutationTaster

Benign

1.0

N;N

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over