chr6-43040959-AATCAGGACAGCT-GC

Variant names:

• chr6-43040959-AATCAGGACAGCT-GC
• NM_014780.5:c.3750_3762delAGCTGTCCTGATTinsGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_014780.5(CUL7):​c.3750_3762delAGCTGTCCTGATTinsGC​(p.Ala1251LeufsTer11) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUL7 NM_014780.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.85
• 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]

KLC4 (HGNC:21624): (kinesin light chain 4) Predicted to be located in cytoplasm and microtubule. Predicted to be part of kinesin complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC124901318 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-43040959-AATCAGGACAGCT-GC is Pathogenic according to our data. Variant chr6-43040959-AATCAGGACAGCT-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 1224473.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	NM_014780.5	MANE Select	c.3750_3762delAGCTGTCCTGATTinsGC	p.Ala1251LeufsTer11	frameshift missense	Exon 20 of 26	NP_055595.2
	CUL7	NM_001168370.2		c.3846_3858delAGCTGTCCTGATTinsGC	p.Ala1283LeufsTer11	frameshift missense	Exon 20 of 26	NP_001161842.2	A0A669KBH4
	CUL7	NM_001374872.1		c.3846_3858delAGCTGTCCTGATTinsGC	p.Ala1283LeufsTer11	frameshift missense	Exon 20 of 26	NP_001361801.1	A0A669KBH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	ENST00000265348.9	TSL:1 MANE Select	c.3750_3762delAGCTGTCCTGATTinsGC	p.Ala1251LeufsTer11	frameshift missense	Exon 20 of 26	ENSP00000265348.4	Q14999-1
	CUL7	ENST00000674100.1		c.3846_3858delAGCTGTCCTGATTinsGC	p.Ala1283LeufsTer11	frameshift missense	Exon 20 of 26	ENSP00000501292.1	A0A669KBH4
	CUL7	ENST00000674134.1		c.3846_3858delAGCTGTCCTGATTinsGC	p.Ala1283LeufsTer11	frameshift missense	Exon 20 of 26	ENSP00000501068.1	A0A669KBH4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

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

Other links and lift over

hg19: chr6-43008697;