11-72232260-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 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 Pathogenic.

• 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

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-72232260-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.1636G>T	p.Val546Phe	missense_variant	Exon 14 of 28	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.1636G>T	p.Val546Phe	missense_variant	Exon 14 of 28	1	NM_001567.4	ENSP00000298229.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-71943304;