rs397514510

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001567.4(INPPL1):​c.1975C>T​(p.Pro659Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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. P659L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

INPPL1
NM_001567.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.50
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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 chr11-72233099-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39473.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
Variant 11-72233098-C-T is Pathogenic according to our data. Variant chr11-72233098-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39477.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INPPL1NM_001567.4 linkuse as main transcriptc.1975C>T p.Pro659Ser missense_variant 17/28 ENST00000298229.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INPPL1ENST00000298229.7 linkuse as main transcriptc.1975C>T p.Pro659Ser missense_variant 17/281 NM_001567.4 P1O15357-1
INPPL1ENST00000538751.5 linkuse as main transcriptc.1249C>T p.Pro417Ser missense_variant 16/271 O15357-2
INPPL1ENST00000541303.5 linkuse as main transcriptn.581C>T non_coding_transcript_exon_variant 3/92
INPPL1ENST00000545355.5 linkuse as main transcriptn.128C>T non_coding_transcript_exon_variant 2/95

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Opsismodysplasia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 10, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;.;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.7
H;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-7.2
D;D;.
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0020
D;D;.
Sift4G
Uncertain
0.0050
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.98
MutPred
0.83
Loss of catalytic residue at P658 (P = 0.0135);.;.;
MVP
0.77
MPC
1.7
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.98
gMVP
0.88

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

LitVar

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

Other links and lift over

dbSNP: rs397514510; hg19: chr11-71944142; API