5-68279741-T-C

Variant names:

• chr5-68279741-T-C
• rs368138177
• NM_181523.3:c.634+8T>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_181523.3(PIK3R1):​c.634+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,613,922 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: PIK3R1 NM_181523.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002553
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.46

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-68279741-T-C is Benign according to our data. Variant chr5-68279741-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 440069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-68279741-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000329 (50/152192) while in subpopulation AMR AF= 0.000655 (10/15278). AF 95% confidence interval is 0.000354. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.634+8T>C		splice_region_variant, intron_variant	Intron 5 of 15	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.634+8T>C		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000359 AC: 90 AN: 250850 Hom.: 0 AF XY: 0.000376 AC XY: 51 AN XY: 135642

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000742

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000434 AC: 635 AN: 1461730 Hom.: 1 Cov.: 31 AF XY: 0.000410 AC XY: 298 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000539

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152192 Hom.: 1 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74344

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000468

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	PIK3R1: BP4, BS2 -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.010
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: rs368138177; hg19: chr5-67575569; COSMIC: COSV104568771; COSMIC: COSV104568771;