rs2135414009

Variant names:

• chr11-72225097-CGGGCCGCGATGGCA-C
• rs2135414009
• NM_001567.4:c.115_128delGGCCGCGATGGCAG

Variant summary

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

The NM_001567.4(INPPL1):​c.115_128delGGCCGCGATGGCAG​(p.Gly39LeufsTer31) variant causes a frameshift 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPPL1 NM_001567.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.85
• 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-72225097-CGGGCCGCGATGGCA-C is Pathogenic according to our data. Variant chr11-72225097-CGGGCCGCGATGGCA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1683469.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001567.4. 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
	INPPL1	NM_001567.4	MANE Select	c.115_128delGGCCGCGATGGCAG	p.Gly39LeufsTer31	frameshift	Exon 1 of 28	NP_001558.3
	INPPL1	NM_001440434.1		c.115_128delGGCCGCGATGGCAG	p.Gly39LeufsTer31	frameshift	Exon 1 of 28	NP_001427363.1
	INPPL1	NM_001440435.1		c.115_128delGGCCGCGATGGCAG	p.Gly39LeufsTer31	frameshift	Exon 2 of 29	NP_001427364.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPPL1	ENST00000298229.7	TSL:1 MANE Select	c.115_128delGGCCGCGATGGCAG	p.Gly39LeufsTer31	frameshift	Exon 1 of 28	ENSP00000298229.2	O15357-1
	INPPL1	ENST00000924957.1		c.115_128delGGCCGCGATGGCAG	p.Gly39LeufsTer31	frameshift	Exon 2 of 29	ENSP00000595016.1
	INPPL1	ENST00000946902.1		c.115_128delGGCCGCGATGGCAG	p.Gly39LeufsTer31	frameshift	Exon 2 of 29	ENSP00000616961.1

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: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Opsismodysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Splicing

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

Other links and lift over

dbSNP: rs2135414009; hg19: chr11-71936141;