6-43038458-G-GA

Variant names:

• chr6-43038458-G-GA
• rs730880301
• NM_014780.5:c.4581dupT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014780.5(CUL7):​c.4581dupT​(p.Arg1528SerfsTer26) 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUL7 NM_014780.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• 3M syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 3-M syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 6-43038458-G-GA is Pathogenic according to our data. Variant chr6-43038458-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 1616.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014780.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	NM_014780.5	MANE Select	c.4581dupT	p.Arg1528SerfsTer26	frameshift	Exon 25 of 26	NP_055595.2
	CUL7	NM_001168370.2		c.4677dupT	p.Arg1560SerfsTer26	frameshift	Exon 25 of 26	NP_001161842.2
	CUL7	NM_001374872.1		c.4677dupT	p.Arg1560SerfsTer26	frameshift	Exon 25 of 26	NP_001361801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	ENST00000265348.9	TSL:1 MANE Select	c.4581dupT	p.Arg1528SerfsTer26	frameshift	Exon 25 of 26	ENSP00000265348.4
	CUL7	ENST00000674100.1		c.4677dupT	p.Arg1560SerfsTer26	frameshift	Exon 25 of 26	ENSP00000501292.1
	CUL7	ENST00000674134.1		c.4677dupT	p.Arg1560SerfsTer26	frameshift	Exon 25 of 26	ENSP00000501068.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Yakut short stature syndrome Pathogenic:1

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs730880301; hg19: chr6-43006196;