chr11-72229116-C-A

Variant names:

• chr11-72229116-C-A
• rs397514509
• NM_001567.4:c.545C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001567.4(INPPL1):​c.545C>A​(p.Ser182*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPPL1 NM_001567.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72229116-C-A is Pathogenic according to our data. Variant chr11-72229116-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39474.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.545C>A	p.Ser182*	stop_gained	Exon 5 of 28	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.545C>A	p.Ser182*	stop_gained	Exon 5 of 28	1	NM_001567.4	ENSP00000298229.2
INPPL1	ENST00000538751	c.-182C>A		5_prime_UTR_variant	Exon 4 of 27	1		ENSP00000444619.1
INPPL1	ENST00000540329	c.-182C>A		5_prime_UTR_variant	Exon 3 of 7	3		ENSP00000440018.1
INPPL1	ENST00000537656	c.-182C>A		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000444630.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Opsismodysplasia Pathogenic:3

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PM2 -

Jan 10, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 08, 2013

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.93
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs397514509; hg19: chr11-71940160;