Genetic Variant INPPL1:p.Ala13ArgfsTer62 (chr11-72225013-C-CG) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001567.4(INPPL1):c.35dupG(p.Ala13ArgfsTer62) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,061,600 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G12G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

INPPL1
NM_001567.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0230

Publications

2 publications found

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]

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

INPPL1 links:

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ACMG classification

Classification was made for transcript

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4 link	c.35dupG	p.Ala13ArgfsTer62	frameshift_variant	Exon 1 of 28	ENST00000298229.7	NP_001558.3	O15357-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPPL1	ENST00000298229.7 link	c.35dupG	p.Ala13ArgfsTer62	frameshift_variant	Exon 1 of 28	1	NM_001567.4	ENSP00000298229.2	O15357-1
INPPL1	ENST00000540973.1 link	c.35dupG	p.Ala13ArgfsTer10	frameshift_variant	Exon 2 of 2	3		ENSP00000440904.1	F5GYK9
INPPL1	ENST00000543234.1 link	c.35dupG	p.Ala13ArgfsTer6	frameshift_variant	Exon 2 of 2	2		ENSP00000440512.1	F5GWY9
INPPL1	ENST00000541544.1 link	n.-56_-55insG		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

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:

0.00000283

AC:

AN:

1061600

Hom.:

Cov.:

AF XY:

0.00000598

AC XY:

AN XY:

501430

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

22144

American (AMR)

AF:

0.00

AC:

AN:

7692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13330

East Asian (EAS)

AF:

0.00

AC:

AN:

24900

South Asian (SAS)

AF:

0.00

AC:

AN:

19476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2820

European-Non Finnish (NFE)

AF:

0.00000330

AC:

AN:

908510

Other (OTH)

AF:

0.00

AC:

AN:

42066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.016044), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.023

Mutation Taster

=9/191

disease causing (fs/PTC)

(source)

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

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11-72225013-CG-CGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over