rs730880261
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014780.5(CUL7):βc.4451_4452delβ(p.Val1484GlyfsTer69) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000075 ( 0 hom. )
Consequence
CUL7
NM_014780.5 frameshift
NM_014780.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.37
Genes affected
CUL7 (HGNC:21024): (cullin 7) The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex. The encoded protein interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-43038680-CCA-C is Pathogenic according to our data. Variant chr6-43038680-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 1615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43038680-CCA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CUL7 | NM_014780.5 | c.4451_4452del | p.Val1484GlyfsTer69 | frameshift_variant | 24/26 | ENST00000265348.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CUL7 | ENST00000265348.9 | c.4451_4452del | p.Val1484GlyfsTer69 | frameshift_variant | 24/26 | 1 | NM_014780.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461808Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727204
GnomAD4 exome
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11
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7
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727204
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
3M syndrome 1 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2009 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breakthrough Genomics, Breakthrough Genomics | - | This variant (reported as c.4450_4451delTG or 4449_4450delTG, in the literature) was previously reported in patients diagnosed with 3M syndrome in homozygous state in five consanguineous families, four from Tunisia and one from Algeria [PMID: 16142236, 19225462]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Breda Genetics srl | Nov 27, 2019 | The variant is reported as pathogenic for 3-M syndrome in ClinVar (Variation ID: 1615). This variant creates a shift in the reading frame, which is predicted to reasult in a premature stop codon 69 amino acids downstream. There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The same mutation has already been described in homozygosity in five consanguineous families, four from Tunisia and one from Algeria by Huber et al., 2005, and in two unrelated patients by Huber et al., 2009 (OMIM * 609577). - |
CUL7-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 22, 2022 | The CUL7 c.4451_4452delTG variant is predicted to result in a frameshift and premature protein termination (p.Val1484Glyfs*69). This variant (also reported as 4449_4450delTG) has frequently been reported in individuals with 3-M syndrome (Huber et al 2005. PubMed ID: 16142236; Huber et al. 2009. PubMed ID: 19225462). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in CUL7 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at