17-8122397-T-C

Variant names:

• chr17-8122397-T-C
• rs387906979
• NM_001165967.2:c.172A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001165967.2(HES7):​c.172A>G​(p.Ile58Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I58R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.68
• Publications: 7 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain bHLH (size 57) in uniprot entity HES7_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-8122397-T-C is Pathogenic according to our data. Variant chr17-8122397-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30698.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES7	NM_001165967.2	c.172A>G	p.Ile58Val	missense_variant	Exon 3 of 4	ENST00000541682.7	NP_001159439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HES7	ENST00000541682.7	c.172A>G	p.Ile58Val	missense_variant	Exon 3 of 4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.172A>G	p.Ile58Val	missense_variant	Exon 3 of 4	1		ENSP00000314774.4
HES7	ENST00000577735.1	c.148A>G	p.Ile50Val	missense_variant	Exon 4 of 5	3		ENSP00000462491.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		3.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.0	N;N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.45
MutPred		0.72		Gain of disorder (P = 0.0446);Gain of disorder (P = 0.0446);.;
MVP		0.94
MPC		1.3
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.51
gMVP		0.39
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906979; hg19: chr17-8025715;