rs398122970

Variant names:

• chr17-8121854-C-CGGGGCGGTTT
• rs398122970
• NM_001165967.2:c.400_409dupAAACCGCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001165967.2(HES7):​c.400_409dupAAACCGCCCC​(p.Arg137GlnfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HES7 NM_001165967.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.73
• Publications: 6 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-8121854-C-CGGGGCGGTTT is Pathogenic according to our data. Variant chr17-8121854-C-CGGGGCGGTTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 91404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HES7	NM_001165967.2	c.400_409dupAAACCGCCCC	p.Arg137GlnfsTer42	frameshift_variant	Exon 4 of 4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.385_394dupAAACCGCCCC	p.Arg132GlnfsTer42	frameshift_variant	Exon 4 of 4		NP_115969.2
HES7	XM_047436940.1	c.496_505dupAAACCGCCCC	p.Arg169GlnfsTer42	frameshift_variant	Exon 3 of 3		XP_047292896.1
HES7	XM_047436941.1	c.487_496dupAAACCGCCCC	p.Arg166GlnfsTer42	frameshift_variant	Exon 5 of 5		XP_047292897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HES7	ENST00000541682.7	c.400_409dupAAACCGCCCC	p.Arg137GlnfsTer42	frameshift_variant	Exon 4 of 4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.385_394dupAAACCGCCCC	p.Arg132GlnfsTer42	frameshift_variant	Exon 4 of 4	1		ENSP00000314774.4
HES7	ENST00000577735.1	c.376_385dupAAACCGCCCC	p.Arg129GlnfsTer20	frameshift_variant	Exon 5 of 5	3		ENSP00000462491.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this premature translational stop signal affects HES7 protein function (PMID: 23897666). This sequence change creates a premature translational stop signal (p.Arg132Glnfs*42) in the HES7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the HES7 protein. This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 23897666; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.400_409dupAAACCGCCCC (p.Arg137GlnfsX42). ClinVar contains an entry for this variant (Variation ID: 91404). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Spondylocostal dysostosis 4, autosomal recessive Pathogenic:1

Sep 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs398122970; hg19: chr17-8025172;