rs2276048

Variant names:

• chr11-72230168-A-G
• rs2276048
• NM_001567.4:c.987A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001567.4(INPPL1):​c.987A>G​(p.Ser329Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,610,878 control chromosomes in the GnomAD database, including 39,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7134 hom., cov: 33)
  • Exomes 𝑓: 0.20 (32628 hom.)
• Consequence: INPPL1 NM_001567.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.77
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-72230168-A-G is Benign according to our data. Variant chr11-72230168-A-G is described in ClinVar as Benign. ClinVar VariationId is 1170422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPPL1	NM_001567.4	c.987A>G	p.Ser329Ser	synonymous_variant	Exon 9 of 28	ENST00000298229.7	NP_001558.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPPL1	ENST00000298229.7	c.987A>G	p.Ser329Ser	synonymous_variant	Exon 9 of 28	1	NM_001567.4	ENSP00000298229.2
INPPL1	ENST00000538751.5	c.261A>G	p.Ser87Ser	synonymous_variant	Exon 8 of 27	1		ENSP00000444619.1
INPPL1	ENST00000540329.5	c.171A>G	p.Ser57Ser	synonymous_variant	Exon 6 of 7	3		ENSP00000440018.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41943 AN: 152140 Hom.: 7131 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.243 AC: 60662 AN: 249322 AF XY: 0.242

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.324

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.199 AC: 290834 AN: 1458620 Hom.: 32628 Cov.: 35 AF XY: 0.203 AC XY: 146981 AN XY: 725010

African (AFR) AF: 0.494 AC: 16509 AN: 33426

American (AMR) AF: 0.249 AC: 11097 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4353 AN: 26032

East Asian (EAS) AF: 0.285 AC: 11299 AN: 39608

South Asian (SAS) AF: 0.348 AC: 29935 AN: 86004

European-Finnish (FIN) AF: 0.206 AC: 10989 AN: 53290

Middle Eastern (MID) AF: 0.280 AC: 1611 AN: 5756

European-Non Finnish (NFE) AF: 0.173 AC: 192022 AN: 1109734

Other (OTH) AF: 0.216 AC: 13019 AN: 60262

GnomAD4 genome AF: 0.276 AC: 41980 AN: 152258 Hom.: 7134 Cov.: 33 AF XY: 0.279 AC XY: 20771 AN XY: 74444

African (AFR) AF: 0.477 AC: 19798 AN: 41540

American (AMR) AF: 0.242 AC: 3703 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 607 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1744 AN: 5176

South Asian (SAS) AF: 0.357 AC: 1723 AN: 4820

European-Finnish (FIN) AF: 0.210 AC: 2225 AN: 10616

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11556 AN: 68006

Other (OTH) AF: 0.241 AC: 509 AN: 2116

Alfa AF: 0.199 Hom.: 7677

Bravo AF: 0.285

Asia WGS AF: 0.379 AC: 1318 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.83
CADD	Benign	0.53
DANN	Benign	0.52
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2276048; hg19: chr11-71941212; COSMIC: COSV53353980; COSMIC: COSV53353980;