rs797044470
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_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
NM_001567.4 frameshift
NM_001567.4 frameshift
Scores
Not classified
Clinical Significance
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]
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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. There are 19 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 | UniProt |
---|---|---|---|---|---|---|---|
INPPL1 | NM_001567.4 | c.94_121del | p.Glu32MetfsTer77 | frameshift_variant | 1/28 | ENST00000298229.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPPL1 | ENST00000298229.7 | c.94_121del | p.Glu32MetfsTer77 | frameshift_variant | 1/28 | 1 | NM_001567.4 | P1 | |
INPPL1 | ENST00000541544.1 | n.10_37del | non_coding_transcript_exon_variant | 1/3 | 2 | ||||
INPPL1 | ENST00000540973.1 | downstream_gene_variant | 3 | ||||||
INPPL1 | ENST00000543234.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151926Hom.: 0 Cov.: 32
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151926Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74198
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Invitae | 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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at