11-72225010-G-C

Variant names:

• chr11-72225010-G-C
• rs1239738293
• NM_001567.4:c.26G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001567.4(INPPL1):​c.26G>C​(p.Gly9Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,058,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. G9D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: INPPL1 NM_001567.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.225
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22516024).

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.26G>C	p.Gly9Ala	missense	Exon 1 of 28	NP_001558.3
	INPPL1	NM_001440434.1		c.26G>C	p.Gly9Ala	missense	Exon 1 of 28	NP_001427363.1
	INPPL1	NM_001440435.1		c.26G>C	p.Gly9Ala	missense	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.26G>C	p.Gly9Ala	missense	Exon 1 of 28	ENSP00000298229.2	O15357-1
	INPPL1	ENST00000924957.1		c.26G>C	p.Gly9Ala	missense	Exon 2 of 29	ENSP00000595016.1
	INPPL1	ENST00000946902.1		c.26G>C	p.Gly9Ala	missense	Exon 2 of 29	ENSP00000616961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000283 AC: 3 AN: 1058904 Hom.: 0 Cov.: 30 AF XY: 0.00000200 AC XY: 1 AN XY: 500126

African (AFR) AF: 0.00 AC: 0 AN: 22046

American (AMR) AF: 0.00 AC: 0 AN: 7584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13220

East Asian (EAS) AF: 0.000122 AC: 3 AN: 24648

South Asian (SAS) AF: 0.00 AC: 0 AN: 19442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2800

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 906762

Other (OTH) AF: 0.00 AC: 0 AN: 41836

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.0051	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.23
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.22
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.28		Loss of catalytic residue at G9 (P = 0.0452)
MVP		0.54
MPC		0.24
ClinPred		0.070	T
GERP RS		1.5
PromoterAI		-0.054	Neutral
Varity_R		0.043
gMVP		0.48
Mutation Taster		=289/11	polymorphism

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: rs1239738293; hg19: chr11-71936054;