rs397514508

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001567.4(INPPL1):c.1976C>T(p.Pro659Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P659S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INPPL1
NM_001567.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.50

Publications

6 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: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-72233098-C-T is described in CliVar as Pathogenic. Clinvar id is 39477.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 11-72233099-C-T is Pathogenic according to our data. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72233099-C-T is described in CliVar as Pathogenic. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4 link	c.1976C>T	p.Pro659Leu	missense_variant	Exon 17 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.1976C>T	p.Pro659Leu	missense_variant	Exon 17 of 28	1	NM_001567.4	ENSP00000298229.2	O15357-1
INPPL1	ENST00000538751.5 link	c.1250C>T	p.Pro417Leu	missense_variant	Exon 16 of 27	1		ENSP00000444619.1	O15357-2
INPPL1	ENST00000541303.5 link	n.582C>T		non_coding_transcript_exon_variant	Exon 3 of 9	2
INPPL1	ENST00000545355.5 link	n.129C>T		non_coding_transcript_exon_variant	Exon 2 of 9	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60392

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000655

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Opsismodysplasia

Pathogenic:2

Jan 08, 2013

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jan 10, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;.;.

PhyloP100

7.5

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.9

D;D;.

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.95

MutPred

0.86

Loss of catalytic residue at P658 (P = 0.0096);.;.;

MVP

0.86

MPC

1.7

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.97

gMVP

0.89

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over