rs878853119

Variant names:

• chr11-72224999-CGGGGCGCCGGGCCCGG-C
• rs878853119
• NM_001567.4:c.24_39delGGGCCCGGGGGGCGCC

Your query was ambiguous. Multiple possible variants found:

• chr11-72224999-CGGGGCGCCGGGCCCGG-C
• chr11-72224999-CGGGGCGCCGGGCCCGG-CGGGGCGCCGGGCCCGGGGGGCGCCGGGCCCGG

Variant summary

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

The NM_001567.4(INPPL1):​c.24_39delGGGCCCGGGGGGCGCC​(p.Gly9TrpfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPPL1 NM_001567.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.793
• Publications: 0 publications found

Genes affected

INPPL1 (HGNC:6080): (inositol polyphosphate phosphatase like 1) The protein encoded by this gene is an SH2-containing 5'-inositol phosphatase that is involved in the regulation of insulin function. The encoded protein also plays a role in the regulation of epidermal growth factor receptor turnover and actin remodelling. Additionally, this gene supports metastatic growth in breast cancer and is a valuable biomarker for breast cancer. [provided by RefSeq, Jan 2009]

INPPL1 Gene-Disease associations (from GenCC):

• opsismodysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• schneckenbecken dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PP5: Variant 11-72224999-CGGGGCGCCGGGCCCGG-C is Pathogenic according to our data. Variant chr11-72224999-CGGGGCGCCGGGCCCGG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 242401.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.24_39delGGGCCCGGGGGGCGCC	p.Gly9TrpfsTer13	frameshift_variant	Exon 1 of 28	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.24_39delGGGCCCGGGGGGCGCC	p.Gly9TrpfsTer13	frameshift_variant	Exon 1 of 28	1	NM_001567.4	ENSP00000298229.2
INPPL1	ENST00000540973.1	c.24_39delGGGCCCGGGGGGCGCC	p.Gly9TrpfsTer9	frameshift_variant	Exon 2 of 2	3		ENSP00000440904.1
INPPL1	ENST00000543234.1	c.24_39delGGGCCCGGGGGGCGCC	p.Gly9TrpfsTer4	frameshift_variant	Exon 2 of 2	2		ENSP00000440512.1
INPPL1	ENST00000541544.1	n.-69_-54delGGGGCGCCGGGCCCGG		upstream_gene_variant		2

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Opsismodysplasia Pathogenic:1

Feb 05, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.24_39del;p.(Gly9Trpfs*13) is a null frameshift variant (NMD) in the INPPL1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This variant is not present in population databases (rs878853119, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs878853119; hg19: chr11-71936043;