Genetic Variant INPPL1:c.182+1G>A (chr11-72225167-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001567.4(INPPL1):c.182+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

INPPL1
NM_001567.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.09

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-72225167-G-A is Pathogenic according to our data. Variant chr11-72225167-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1499246.Status of the report is criteria_provided_single_submitter, 1 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	Effect	Exon Rank	Protein
INPPL1	NM_001567.4	MANE Select	c.182+1G>A	splice_donor intron	N/A	NP_001558.3
INPPL1	NM_001440434.1		c.182+1G>A	splice_donor intron	N/A	NP_001427363.1
INPPL1	NM_001440435.1		c.182+1G>A	splice_donor intron	N/A	NP_001427364.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
INPPL1	ENST00000298229.7	TSL:1 MANE Select	c.182+1G>A	splice_donor intron	N/A	ENSP00000298229.2	O15357-1
INPPL1	ENST00000924957.1		c.182+1G>A	splice_donor intron	N/A	ENSP00000595016.1
INPPL1	ENST00000946902.1		c.182+1G>A	splice_donor intron	N/A	ENSP00000616961.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

2538

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1078878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

509518

African (AFR)

AF:

0.00

AC:

AN:

22996

American (AMR)

AF:

0.00

AC:

AN:

8516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14270

East Asian (EAS)

AF:

0.00

AC:

AN:

26680

South Asian (SAS)

AF:

0.00

AC:

AN:

19634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2942

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

919172

Other (OTH)

AF:

0.00

AC:

AN:

43566

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.77

PhyloP100

4.1

GERP RS

2.8

PromoterAI

-0.087

Neutral

(source)

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: -48

DS_DL_spliceai

0.97

Position offset: -1

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