rs746647683

Positions:

• chr11-72229676-CAG-C

Variant summary

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

The NM_001567.4(INPPL1):​c.768_769del​(p.Glu258AlafsTer45) variant causes a frameshift change. The variant allele was found at a frequency of 0.000013 in 1,613,940 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: INPPL1 NM_001567.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.40

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72229676-CAG-C is Pathogenic according to our data. Variant chr11-72229676-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPPL1	NM_001567.4	c.768_769del	p.Glu258AlafsTer45	frameshift_variant	7/28	ENST00000298229.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPPL1	ENST00000298229.7	c.768_769del	p.Glu258AlafsTer45	frameshift_variant	7/28	1	NM_001567.4	P1
INPPL1	ENST00000538751.5	c.42_43del	p.Glu16AlafsTer45	frameshift_variant	6/27	1
INPPL1	ENST00000537656.1	c.42_43del	p.Glu16AlafsTer?	frameshift_variant	3/3	2
INPPL1	ENST00000540329.5	c.27+119_27+120del		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251386 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461792 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727194

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: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28869677, 23273567) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 235824). This sequence change creates a premature translational stop signal (p.Glu258Alafs*45) 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). This variant is present in population databases (rs746647683, ExAC 0.02%). This premature translational stop signal has been observed in individual(s) with opsismodysplasia (PMID: 23273567, 28869677). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. -

Opsismodysplasia Pathogenic:2

Pathogenic, no assertion criteria provided	research	Cormier-Daire Lab, IMAGINE	-	- -
Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jan 08, 2013	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs746647683; hg19: chr11-71940720;