rs878853120

Variant names:

• chr11-72229558-G-C
• rs878853120
• NM_001567.4:c.753G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001567.4(INPPL1):​c.753G>C​(p.Gln251His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. Q251Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPPL1 NM_001567.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.753G>C	p.Gln251His	missense_variant, splice_region_variant	Exon 6 of 28	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.753G>C	p.Gln251His	missense_variant, splice_region_variant	Exon 6 of 28	1	NM_001567.4	ENSP00000298229.2
INPPL1	ENST00000538751.5	c.27G>C	p.Gln9His	missense_variant, splice_region_variant	Exon 5 of 27	1		ENSP00000444619.1
INPPL1	ENST00000540329.5	c.27G>C	p.Gln9His	missense_variant, splice_region_variant	Exon 4 of 7	3		ENSP00000440018.1
INPPL1	ENST00000537656.1	c.27G>C	p.Gln9His	missense_variant, splice_region_variant	Exon 2 of 3	2		ENSP00000444630.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;T;T;T
Eigen	Benign	0.0021
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.
PhyloP100		4.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N;N;.;N;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.017	D;D;.;D;.
Sift4G	Benign	0.46	T;D;T;T;D
Polyphen		0.0010	B;.;.;.;.
Vest4		0.44
MutPred		0.25		Gain of catalytic residue at L253 (P = 0.0576);.;.;.;.;
MVP		0.84
MPC		0.44
ClinPred		0.89	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.40
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 26
DS_DL_spliceai		0.97		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878853120; hg19: chr11-71940602; COSMIC: COSV53353683; COSMIC: COSV53353683;