5-68279720-T-C

Position:

• chr5-68279720-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_181523.3(PIK3R1):​c.621T>C​(p.Ile207Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,613,960 control chromosomes in the GnomAD database, including 1,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (98 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1101 hom.)
• Consequence: PIK3R1 NM_181523.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.795

Genes affected

PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-68279720-T-C is Benign according to our data. Variant chr5-68279720-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 159724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.795 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.029 (4413/152310) while in subpopulation SAS AF= 0.0504 (243/4824). AF 95% confidence interval is 0.0452. There are 98 homozygotes in gnomad4. There are 2183 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 98 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.621T>C	p.Ile207Ile	synonymous_variant	5/16	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.621T>C	p.Ile207Ile	synonymous_variant	5/16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4414 AN: 152190 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0352 AC: 8835 AN: 251160 Hom.: 192 AF XY: 0.0375 AC XY: 5090 AN XY: 135760

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.0474

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0630

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0360 AC: 52561 AN: 1461650 Hom.: 1101 Cov.: 32 AF XY: 0.0371 AC XY: 26974 AN XY: 727152

Gnomad4 AFR exome AF: 0.00499

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.0447

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0496

Gnomad4 FIN exome AF: 0.0633

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0290 AC: 4413 AN: 152310 Hom.: 98 Cov.: 32 AF XY: 0.0293 AC XY: 2183 AN XY: 74472

Gnomad4 AFR AF: 0.00582

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0504

Gnomad4 FIN AF: 0.0557

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0367 Hom.: 65

Bravo AF: 0.0249

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0400

EpiControl AF: 0.0422

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2013	- -

SHORT syndrome;C3554689:Agammaglobulinemia 7, autosomal recessive;C4014934:Immunodeficiency 36 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.7
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749601; hg19: chr5-67575548; COSMIC: COSV57128723; COSMIC: COSV57128723;