rs878853122

Variant names:

• chr11-72225013-CG-C
• rs878853122
• NM_001567.4:c.35delG

Your query was ambiguous. Multiple possible variants found:

• chr11-72225013-CG-C
• chr11-72225013-CG-CGG

Variant summary

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

The NM_001567.4(INPPL1):​c.35delG​(p.Gly12AlafsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000942 in 1,061,596 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: INPPL1 NM_001567.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 0 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: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPPL1	NM_001567.4	MANE Select	c.35delG	p.Gly12AlafsTer15	frameshift	Exon 1 of 28	NP_001558.3
	INPPL1	NM_001440434.1		c.35delG	p.Gly12AlafsTer15	frameshift	Exon 1 of 28	NP_001427363.1
	INPPL1	NM_001440435.1		c.35delG	p.Gly12AlafsTer15	frameshift	Exon 2 of 29	NP_001427364.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPPL1	ENST00000298229.7	TSL:1 MANE Select	c.35delG	p.Gly12AlafsTer15	frameshift	Exon 1 of 28	ENSP00000298229.2	O15357-1
	INPPL1	ENST00000924957.1		c.35delG	p.Gly12AlafsTer15	frameshift	Exon 2 of 29	ENSP00000595016.1
	INPPL1	ENST00000946902.1		c.35delG	p.Gly12AlafsTer15	frameshift	Exon 2 of 29	ENSP00000616961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 322 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000942 AC: 10 AN: 1061596 Hom.: 0 Cov.: 30 AF XY: 0.0000120 AC XY: 6 AN XY: 501424

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22144

American (AMR) AF: 0.00 AC: 0 AN: 7692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13332

East Asian (EAS) AF: 0.0000402 AC: 1 AN: 24900

South Asian (SAS) AF: 0.00 AC: 0 AN: 19474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2820

European-Non Finnish (NFE) AF: 0.00000881 AC: 8 AN: 908508

Other (OTH) AF: 0.0000238 AC: 1 AN: 42066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000414346), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.023

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

Other links and lift over

dbSNP: rs878853122; hg19: chr11-71936057;