chr11-72234616-G-C

Variant names:

• chr11-72234616-G-C
• rs655423
• NM_001567.4:c.2415+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001567.4(INPPL1):​c.2415+1G>C 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: INPPL1 NM_001567.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.63
• Publications: 4 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.7, offset of 31, new splice context is: tggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPPL1	NM_001567.4	MANE Select	c.2415+1G>C		splice_donor intron	N/A	NP_001558.3
	INPPL1	NM_001440434.1		c.2481+1G>C		splice_donor intron	N/A	NP_001427363.1
	INPPL1	NM_001440435.1		c.2415+1G>C		splice_donor intron	N/A	NP_001427364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPPL1	ENST00000298229.7	TSL:1 MANE Select	c.2415+1G>C		splice_donor intron	N/A	ENSP00000298229.2
	INPPL1	ENST00000538751.5	TSL:1	c.1689+1G>C		splice_donor intron	N/A	ENSP00000444619.1
	INPPL1	ENST00000535985.1	TSL:2	n.*143+1G>C		splice_donor intron	N/A	ENSP00000437852.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		5.6
GERP RS		5.5
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: 30
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs655423; hg19: chr11-71945660;