NM_001567.4:c.753G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001567.4(INPPL1):​c.753G>C​(p.Gln251His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as no classification for the single variant (no stars). Synonymous variant affecting the same amino acid position (i.e. Q251Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

INPPL1
NM_001567.4 missense, splice_region

Scores

3
8
8
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.63
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 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INPPL1NM_001567.4 linkc.753G>C p.Gln251His missense_variant, splice_region_variant Exon 6 of 28 ENST00000298229.7 NP_001558.3 O15357-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INPPL1ENST00000298229.7 linkc.753G>C p.Gln251His missense_variant, splice_region_variant Exon 6 of 28 1 NM_001567.4 ENSP00000298229.2 O15357-1
INPPL1ENST00000538751.5 linkc.27G>C p.Gln9His missense_variant, splice_region_variant Exon 5 of 27 1 ENSP00000444619.1 O15357-2
INPPL1ENST00000540329.5 linkc.27G>C p.Gln9His missense_variant, splice_region_variant Exon 4 of 7 3 ENSP00000440018.1 F5GY16
INPPL1ENST00000537656.1 linkc.27G>C p.Gln9His missense_variant, splice_region_variant Exon 2 of 3 2 ENSP00000444630.1 F5H588

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
35
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T;.;T;T;T
Eigen
Benign
0.0021
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.84
T;T;T;T;T
M_CAP
Pathogenic
0.40
D
MetaRNN
Benign
0.24
T;T;T;T;T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.3
M;.;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.3
N;N;.;N;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.017
D;D;.;D;.
Sift4G
Benign
0.46
T;D;T;T;D
Polyphen
0.0010
B;.;.;.;.
Vest4
0.44
MutPred
0.25
Gain of catalytic residue at L253 (P = 0.0576);.;.;.;.;
MVP
0.84
MPC
0.44
ClinPred
0.89
D
GERP RS
4.8
Varity_R
0.13
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.45
Position offset: 26
DS_DL_spliceai
0.97
Position offset: 0

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: rs878853120; hg19: chr11-71940602; COSMIC: COSV53353683; COSMIC: COSV53353683; API