11-72224999-CGGGGCGCCGGGCCCGG-CGGGGCGCCGGGCCCGGGGGGCGCCGGGCCCGG

Variant names:

• chr11-72224999-C-CGGGGCGCCGGGCCCGG
• rs878853119
• NM_001567.4:c.24_39dupGGGCCCGGGGGGCGCC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001567.4(INPPL1):​c.24_39dupGGGCCCGGGGGGCGCC​(p.Leu14GlyfsTer66) 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPPL1 NM_001567.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248
• 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: Likely_pathogenic. The variant received 8 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 28 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.24_39dupGGGCCCGGGGGGCGCC	p.Leu14GlyfsTer66	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_39dupGGGCCCGGGGGGCGCC	p.Leu14GlyfsTer66	frameshift_variant	Exon 1 of 28	1	NM_001567.4	ENSP00000298229.2
INPPL1	ENST00000540973.1	c.24_39dupGGGCCCGGGGGGCGCC	p.Leu14GlyfsTer14	frameshift_variant	Exon 2 of 2	3		ENSP00000440904.1
INPPL1	ENST00000543234.1	c.24_39dupGGGCCCGGGGGGCGCC	p.Leu14GlyfsTer10	frameshift_variant	Exon 2 of 2	2		ENSP00000440512.1
INPPL1	ENST00000541544.1	n.-70_-69insGGGGCGCCGGGCCCGG		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25

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;