6-43040971-T-TTGCAGGCATTGCTGCAGCTGTGCCAGCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014780.5(CUL7):c.3749_3750insGGCTGGCACAGCTGCAGCAATGCCTGCA(p.Val1252GlyfsTer23) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CUL7 NM_014780.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 6-43040971-T-TTGCAGGCATTGCTGCAGCTGTGCCAGCC is Pathogenic according to our data. Variant chr6-43040971-T-TTGCAGGCATTGCTGCAGCTGTGCCAGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 800566.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL7	NM_014780.5	c.3749_3750insGGCTGGCACAGCTGCAGCAATGCCTGCA	p.Val1252GlyfsTer23	frameshift_variant	20/26	ENST00000265348.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL7	ENST00000265348.9	c.3749_3750insGGCTGGCACAGCTGCAGCAATGCCTGCA	p.Val1252GlyfsTer23	frameshift_variant	20/26	1	NM_014780.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461026 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726730

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

3M syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Prenatal Diagnosis Center, Guizhou Provincial People's Hospital

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs766471384; hg19: chr6-43008709;