rs730880261

Positions:

• chr6-43038680-CCA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014780.5(CUL7):​c.4451_4452delTG​(p.Val1484fs) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CUL7 NM_014780.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

CUL7 (HGNC:):

ACMG classification

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	Protein	UniProt
CUL7	NM_014780.5	c.4451_4452delTG	p.Val1484fs	frameshift_variant	24/26	ENST00000265348.9	NP_055595.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9	c.4451_4452delTG	p.Val1484fs	frameshift_variant	24/26	1	NM_014780.5	ENSP00000265348.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461808 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3M syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Oct 17, 2020	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, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs730880261; hg19: chr6-43006418;