chr10-87863959-G-A

Variant names:

• chr10-87863959-G-A
• rs12573787
• NM_000314.8:c.-511G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP2 BP4_Moderate BP6_Very_Strong BA1

The NM_001304717.5(PTEN):​c.10G>A​(p.Gly4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 381,510 control chromosomes in the GnomAD database, including 4,826 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 Likely benign (★★). The gene PTEN is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.13 (1493 hom., cov: 31)
  • Exomes 𝑓: 0.15 (3333 hom.)
• Consequence: PTEN NM_001304717.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 2.14
• Publications: 24 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]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for PTEN are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -17 ACMG points.

• PP2: Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.001 (above the threshold of 3.09). GenCC associations: The gene is linked to Cowden syndrome 1, PTEN hamartoma tumor syndrome, macrocephaly-autism syndrome, glioma susceptibility 2, activated PI3K-delta syndrome, Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, leiomyosarcoma, Cowden disease, renal cell carcinoma, Proteus-like syndrome.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 10-87863959-G-A is Benign according to our data. Variant chr10-87863959-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 810888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304717.5. 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.-511G>A		5_prime_UTR	Exon 1 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.10G>A	p.Gly4Arg	missense	Exon 1 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.-1216G>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.-511G>A		5_prime_UTR	Exon 1 of 9	ENSP00000361021.3	P60484-1
	PTEN	ENST00000693560.1		c.10G>A	p.Gly4Arg	missense	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000700029.2		c.-511G>A		5_prime_UTR	Exon 1 of 10	ENSP00000514759.2	A0A8V8TPK6

Frequencies

GnomAD3 genomes AF: 0.126 AC: 18970 AN: 150292 Hom.: 1491 Cov.: 31

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.154 AC: 35529 AN: 231108 Hom.: 3333 Cov.: 0 AF XY: 0.152 AC XY: 18136 AN XY: 119532

African (AFR) AF: 0.0618 AC: 389 AN: 6294

American (AMR) AF: 0.213 AC: 1402 AN: 6590

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 911 AN: 8120

East Asian (EAS) AF: 0.349 AC: 7648 AN: 21894

South Asian (SAS) AF: 0.130 AC: 417 AN: 3202

European-Finnish (FIN) AF: 0.113 AC: 2260 AN: 19954

Middle Eastern (MID) AF: 0.0794 AC: 93 AN: 1172

European-Non Finnish (NFE) AF: 0.135 AC: 20128 AN: 149084

Other (OTH) AF: 0.154 AC: 2281 AN: 14798

GnomAD4 genome AF: 0.126 AC: 18981 AN: 150402 Hom.: 1493 Cov.: 31 AF XY: 0.127 AC XY: 9318 AN XY: 73528

African (AFR) AF: 0.0615 AC: 2524 AN: 41012

American (AMR) AF: 0.193 AC: 2935 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 416 AN: 3450

East Asian (EAS) AF: 0.349 AC: 1745 AN: 5004

South Asian (SAS) AF: 0.124 AC: 593 AN: 4772

European-Finnish (FIN) AF: 0.109 AC: 1119 AN: 10308

Middle Eastern (MID) AF: 0.127 AC: 36 AN: 284

European-Non Finnish (NFE) AF: 0.138 AC: 9270 AN: 67398

Other (OTH) AF: 0.138 AC: 290 AN: 2106

Alfa AF: 0.0599 Hom.: 63

Bravo AF: 0.131

Asia WGS AF: 0.212 AC: 730 AN: 3438

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C2931456:Familial prostate cancer;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)
1	-	-	Myeloproliferative neoplasm, unclassifiable (1)
-	-	1	PTEN hamartoma tumor syndrome (1)
-	-	1	PTEN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
PhyloP100		2.1
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=279/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12573787; hg19: chr10-89623716;