NM_000314.8:c.-765G>A

Variant names:

• chr10-87863705-G-A
• rs587776674
• NM_000314.8:c.-765G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: PTEN c.-765G>A (AKA c.-764G>A, NC_000010.10:g.89623462G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000567/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: PTEN NM_000314.8 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:8
• Conservation: PhyloP100: 1.84
• Publications: 5 publications found

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]

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]

KLLN Gene-Disease associations (from GenCC):

• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 4

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

MLDHR (HGNC:55481):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.-765G>A		5_prime_UTR	Exon 1 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.-245G>A		5_prime_UTR	Exon 1 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.-1470G>A		5_prime_UTR	Exon 1 of 9	NP_001291647.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.-765G>A		5_prime_UTR	Exon 1 of 9	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.-245G>A		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.-765G>A		5_prime_UTR	Exon 1 of 10	ENSP00000514759.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000498 AC: 12 AN: 241100 Hom.: 0 Cov.: 0 AF XY: 0.0000571 AC XY: 7 AN XY: 122556

African (AFR) AF: 0.00 AC: 0 AN: 6882

American (AMR) AF: 0.00 AC: 0 AN: 7220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8930

East Asian (EAS) AF: 0.00 AC: 0 AN: 22566

South Asian (SAS) AF: 0.00 AC: 0 AN: 3010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20756

Middle Eastern (MID) AF: 0.000790 AC: 1 AN: 1266

European-Non Finnish (NFE) AF: 0.0000647 AC: 10 AN: 154550

Other (OTH) AF: 0.0000628 AC: 1 AN: 15920

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74412

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000100 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	2	-	PTEN hamartoma tumor syndrome (3)
1	1	-	Cowden syndrome 1 (2)
-	1	-	Glioma susceptibility 2 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Prostate cancer;C1848599:VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;C1959582:PTEN hamartoma tumor syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		1.8
PromoterAI		0.0040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/200	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587776674; hg19: chr10-89623462;