rs1044322

Positions:

• chr10-87863566-G-A
• chr10-87863566-G-C
• chr10-87863566-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000692337.1(ENSG00000289051):​c.8G>A​(p.Arg3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 386,948 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.015 (41 hom.)
• Consequence: ENST00000692337.1 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 1.84

Genes affected

(HGNC:):

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-87863566-G-A is Benign according to our data. Variant chr10-87863566-G-A is described in ClinVar as [Benign]. Clinvar id is 138837.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87863566-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1871/152120) while in subpopulation NFE AF= 0.0167 (1133/67952). AF 95% confidence interval is 0.0159. There are 22 homozygotes in gnomad4. There are 879 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2			upstream_gene_variant		ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000692337.1	c.8G>A	p.Arg3Gln	missense_variant	1/1			P1
PTEN	ENST00000693560.1	c.-384G>A		5_prime_UTR_variant	1/10
PTEN	ENST00000688308.1	c.-17+453G>A		intron_variant				P1
KLLN	ENST00000445946.5			upstream_gene_variant			NM_001126049.2	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1872 AN: 152012 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0155 AC: 3630 AN: 234828 Hom.: 41 Cov.: 0 AF XY: 0.0157 AC XY: 1880 AN XY: 119370

Gnomad4 AFR exome AF: 0.00603

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0203

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.00431

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0123 AC: 1871 AN: 152120 Hom.: 22 Cov.: 32 AF XY: 0.0118 AC XY: 879 AN XY: 74362

Gnomad4 AFR AF: 0.00599

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00832 Hom.: 3

Bravo AF: 0.0120

Asia WGS AF: 0.00409 AC: 14 AN: 3440

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 30, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2020

The c.-903G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 903 bases upstream from the first translated codon. This variant is located in the promoter region of the PTEN gene, but its potential impact on PTEN regulation has not yet been investigated (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

PTEN hamartoma tumor syndrome Benign:1

Benign, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Sep 14, 2016

PTEN c.-903G>A (NC_000010.10:g.89623323G>A) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BA1: Allele frequency of 0.011 (1.1%, 343/30,808 alleles) in the gnomAD cohort. (PMID 27535533) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.96

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: rs1044322; hg19: chr10-89623323;