11-72230337-A-G

Variant names:

• chr11-72230337-A-G
• rs2276047
• NM_001567.4:c.1091-25A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001567.4(INPPL1):​c.1091-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,613,394 control chromosomes in the GnomAD database, including 54,263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.33 (10116 hom., cov: 33)
  • Exomes 𝑓: 0.23 (44147 hom.)
• Consequence: INPPL1 NM_001567.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.252
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-72230337-A-G is Benign according to our data. Variant chr11-72230337-A-G is described in ClinVar as Benign. ClinVar VariationId is 1289494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.1091-25A>G		intron_variant	Intron 9 of 27	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.1091-25A>G		intron_variant	Intron 9 of 27	1	NM_001567.4	ENSP00000298229.2
INPPL1	ENST00000538751.5	c.365-25A>G		intron_variant	Intron 8 of 26	1		ENSP00000444619.1
INPPL1	ENST00000540329.5	c.275-25A>G		intron_variant	Intron 6 of 6	3		ENSP00000440018.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49533 AN: 152104 Hom.: 10093 Cov.: 33

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.279 AC: 69816 AN: 250574 AF XY: 0.277

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.403

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.231 AC: 337976 AN: 1461172 Hom.: 44147 Cov.: 35 AF XY: 0.235 AC XY: 170674 AN XY: 726910

African (AFR) AF: 0.598 AC: 20002 AN: 33470

American (AMR) AF: 0.268 AC: 11986 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4878 AN: 26116

East Asian (EAS) AF: 0.354 AC: 14059 AN: 39692

South Asian (SAS) AF: 0.386 AC: 33296 AN: 86216

European-Finnish (FIN) AF: 0.219 AC: 11688 AN: 53378

Middle Eastern (MID) AF: 0.319 AC: 1767 AN: 5540

European-Non Finnish (NFE) AF: 0.202 AC: 224862 AN: 1111742

Other (OTH) AF: 0.256 AC: 15438 AN: 60346

GnomAD4 genome AF: 0.326 AC: 49607 AN: 152222 Hom.: 10116 Cov.: 33 AF XY: 0.328 AC XY: 24416 AN XY: 74420

African (AFR) AF: 0.575 AC: 23860 AN: 41526

American (AMR) AF: 0.269 AC: 4125 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 668 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2155 AN: 5156

South Asian (SAS) AF: 0.400 AC: 1930 AN: 4830

European-Finnish (FIN) AF: 0.218 AC: 2308 AN: 10608

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13753 AN: 67998

Other (OTH) AF: 0.284 AC: 600 AN: 2112

Alfa AF: 0.253 Hom.: 1163

Bravo AF: 0.338

Asia WGS AF: 0.456 AC: 1584 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Opsismodysplasia Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.47
PhyloP100		-0.25
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2276047; hg19: chr11-71941381;