chr11-72225034-A-G

Variant names:

• chr11-72225034-A-G
• rs1948628587
• NM_001567.4:c.50A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_001567.4(INPPL1):​c.50A>G​(p.Gln17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,074,498 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. Q17L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: INPPL1 NM_001567.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.209
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22298017).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000102 (11/1074498) while in subpopulation SAS AF = 0.000508 (10/19688). AF 95% confidence interval is 0.000275. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.50A>G	p.Gln17Arg	missense	Exon 1 of 28	NP_001558.3
	INPPL1	NM_001440434.1		c.50A>G	p.Gln17Arg	missense	Exon 1 of 28	NP_001427363.1
	INPPL1	NM_001440435.1		c.50A>G	p.Gln17Arg	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.50A>G	p.Gln17Arg	missense	Exon 1 of 28	ENSP00000298229.2	O15357-1
	INPPL1	ENST00000924957.1		c.50A>G	p.Gln17Arg	missense	Exon 2 of 29	ENSP00000595016.1
	INPPL1	ENST00000946902.1		c.50A>G	p.Gln17Arg	missense	Exon 2 of 29	ENSP00000616961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000102 AC: 11 AN: 1074498 Hom.: 0 Cov.: 30 AF XY: 0.0000118 AC XY: 6 AN XY: 508106

African (AFR) AF: 0.00 AC: 0 AN: 22582

American (AMR) AF: 0.00 AC: 0 AN: 8136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13966

East Asian (EAS) AF: 0.00 AC: 0 AN: 26112

South Asian (SAS) AF: 0.000508 AC: 10 AN: 19688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2902

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 916984

Other (OTH) AF: 0.0000232 AC: 1 AN: 43082

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.75
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.17	N
PhyloP100		0.21
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.24
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.23		Gain of MoRF binding (P = 0.0119)
MVP		0.36
MPC		0.24
ClinPred		0.31	T
GERP RS		-0.22
PromoterAI		-0.043	Neutral
Varity_R		0.054
gMVP		0.26
Mutation Taster		=96/4	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: rs1948628587; hg19: chr11-71936078;