Genetic Variant NM_001567.4:c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG (chr11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Publications

1 publications found

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 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

INPPL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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.

PP5

Variant 11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C is Pathogenic according to our data. Variant chr11-72225070-CGGCCGCGGAGGAGCTGCTGGCCCGGGCG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 39481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001567.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INPPL1	NM_001567.4	MANE Select	c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift	Exon 1 of 28	NP_001558.3
INPPL1	NM_001440434.1		c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift	Exon 1 of 28	NP_001427363.1
INPPL1	NM_001440435.1		c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift	Exon 2 of 29	NP_001427364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INPPL1	ENST00000298229.7	TSL:1 MANE Select	c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift	Exon 1 of 28	ENSP00000298229.2	O15357-1
INPPL1	ENST00000924957.1		c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift	Exon 2 of 29	ENSP00000595016.1
INPPL1	ENST00000946902.1		c.94_121delGAGGAGCTGCTGGCCCGGGCGGGCCGCG	p.Glu32MetfsTer77	frameshift	Exon 2 of 29	ENSP00000616961.1

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

African (AFR)

AF:

0.0000241

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Opsismodysplasia (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.8

Mutation Taster

=16/184

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over