rs398122970

Positions:

• chr17-8121854-C-CGGGGCGGTTT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001165967.2(HES7):​c.400_409dupAAACCGCCCC​(p.Arg137fs) 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 91404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HES7	NM_001165967.2	c.400_409dupAAACCGCCCC	p.Arg137fs	frameshift_variant	4/4	ENST00000541682.7	NP_001159439.1
HES7	NM_032580.4	c.385_394dupAAACCGCCCC	p.Arg132fs	frameshift_variant	4/4		NP_115969.2
HES7	XM_047436940.1	c.496_505dupAAACCGCCCC	p.Arg169fs	frameshift_variant	3/3		XP_047292896.1
HES7	XM_047436941.1	c.487_496dupAAACCGCCCC	p.Arg166fs	frameshift_variant	5/5		XP_047292897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HES7	ENST00000541682.7	c.400_409dupAAACCGCCCC	p.Arg137fs	frameshift_variant	4/4	1	NM_001165967.2	ENSP00000446205.2
HES7	ENST00000317814.8	c.385_394dupAAACCGCCCC	p.Arg132fs	frameshift_variant	4/4	1		ENSP00000314774.4
HES7	ENST00000577735.1	c.376_385dupAAACCGCCCC	p.Arg129fs	frameshift_variant	5/5	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2021

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. Experimental studies have shown that this premature translational stop signal affects HES7 protein function (PMID: 23897666). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 91404). This variant is also known as c.400_409dupAAACCGCCCC (p.Arg137GlnfsX42). 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 not present in population databases (ExAC no frequency). 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. -

Spondylocostal dysostosis 4, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122970; hg19: chr17-8025172;