dbSNP rs797044470: INPPL1:p.Glu32MetfsTer77 (chr11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001567.4(INPPL1):c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG(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
NM_001567.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.80

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.975 CDS is truncated, and there are 2 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 rank	MANE	Protein	UniProt
INPPL1	NM_001567.4 link	c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift_variant	Exon 1 of 28	ENST00000298229.7	NP_001558.3	O15357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPPL1	ENST00000298229.7 link	c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift_variant	Exon 1 of 28	1	NM_001567.4	ENSP00000298229.2	O15357-1
INPPL1	ENST00000541544.1 link	n.10_37delGAGGAGCTGCTGGCCCGGGCGGGCCGCG		non_coding_transcript_exon_variant	Exon 1 of 3	2
INPPL1	ENST00000540973.1 link	c.20_47delGGCCGCGGAGGAGCTGCTGGCCCGGGCG		downstream_gene_variant		3		ENSP00000440904.1	F5GYK9
INPPL1	ENST00000543234.1 link	c.34_61delGGCCGCGGAGGAGCTGCTGGCCCGGGCG		downstream_gene_variant		2		ENSP00000440512.1	F5GWY9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

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:

AN:

151926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74198

show subpopulations

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

LINK: link

Submissions by phenotype

Opsismodysplasia

Pathogenic:2

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with INPPL1-related conditions (PMID: 23273569, 34529350). ClinVar contains an entry for this variant (Variation ID: 39481). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over