Genetic Variant NM_014780.5:c.4451_4452delTG (chr6-43038680-CCA-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014780.5(CUL7):c.4451_4452delTG(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 (★★). 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.37

Variant links:

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 links:

Genome browser will be placed here

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 rank	MANE	Protein	UniProt
CUL7	NM_014780.5 link	c.4451_4452delTG	p.Val1484GlyfsTer69	frameshift_variant	Exon 24 of 26	ENST00000265348.9	NP_055595.2	Q14999-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL7	ENST00000265348.9 link	c.4451_4452delTG	p.Val1484GlyfsTer69	frameshift_variant	Exon 24 of 26	1	NM_014780.5	ENSP00000265348.4		Q14999-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461808

Hom.:

AF XY:

0.00000963

AC XY:

AN XY:

727204

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3M syndrome 1

Pathogenic:3

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 17, 2020

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Nov 27, 2019

Breda Genetics srl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over