rs797044470

Positions:

• chr11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000298229.7(INPPL1):​c.94_121del​(p.Glu32MetfsTer77) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000658 in 151,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: INPPL1 ENST00000298229.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C is Pathogenic according to our data. Variant chr11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 39481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.94_121del	p.Glu32MetfsTer77	frameshift_variant	1/28	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.94_121del	p.Glu32MetfsTer77	frameshift_variant	1/28	1	NM_001567.4	ENSP00000298229	P1
INPPL1	ENST00000541544.1	n.10_37del		non_coding_transcript_exon_variant	1/3	2
INPPL1	ENST00000540973.1			downstream_gene_variant		3		ENSP00000440904
INPPL1	ENST00000543234.1			downstream_gene_variant		2		ENSP00000440512

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151926 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151926 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74198

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Opsismodysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 10, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39481). This premature translational stop signal has been observed in individuals with INPPL1-related conditions (PMID: 23273569, 34529350). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu32Metfs*77) in the INPPL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in INPPL1 are known to be pathogenic (PMID: 23273567, 23273569). -

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: rs797044470; hg19: chr11-71936114;