rs1234219

chr10-87889820-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000314.8(PTEN):c.80-4205A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 152,198 control chromosomes in the GnomAD database, including 408 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.066 (408 hom., cov: 32)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.285

Genes affected

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.80-4205A>G		intron_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.599-4205A>G		intron_variant
PTEN	NM_001304718.2	c.-625-4205A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.80-4205A>G		intron_variant		1	NM_000314.8	P1

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9967 AN: 152080 Hom.: 407 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0606

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0490

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0717

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0655 AC: 9973 AN: 152198 Hom.: 408 Cov.: 32 AF XY: 0.0664 AC XY: 4941 AN XY: 74402

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.0606

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.0493

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0702

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0738 Hom.: 237

Bravo AF: 0.0702

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	6.4
Dann	Benign	0.68

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: rs1234219; hg19: chr10-89649577;