rs878853120

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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).

• 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

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
• PP3: Splicing scoreres supports a deletorius 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;.;.;.;.
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

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

Publications

LitVar

Other links and lift over

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