11-72232260-G-T

Variant names:

• chr11-72232260-G-T
• rs376117918
• NM_001567.4:c.1636G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001567.4(INPPL1):​c.1636G>T​(p.Val546Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,404,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V546I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INPPL1 NM_001567.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

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.1636G>T	p.Val546Phe	missense	Exon 14 of 28	NP_001558.3
	INPPL1	NM_001440434.1		c.1702G>T	p.Val568Phe	missense	Exon 14 of 28	NP_001427363.1
	INPPL1	NM_001440435.1		c.1636G>T	p.Val546Phe	missense	Exon 15 of 29	NP_001427364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPPL1	ENST00000298229.7	TSL:1 MANE Select	c.1636G>T	p.Val546Phe	missense	Exon 14 of 28	ENSP00000298229.2
	INPPL1	ENST00000538751.5	TSL:1	c.910G>T	p.Val304Phe	missense	Exon 13 of 27	ENSP00000444619.1
	INPPL1	ENST00000537755.1	TSL:4	n.187G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1404766 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693334

⚠️ 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: 32084

American (AMR) AF: 0.00 AC: 0 AN: 36234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.00 AC: 0 AN: 36586

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081500

Other (OTH) AF: 0.00 AC: 0 AN: 58228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.66		Loss of ubiquitination at K541 (P = 0.1403)
MVP		0.77
MPC		1.7
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.93
Mutation Taster		=43/57	disease causing

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: rs376117918; hg19: chr11-71943304;