rs1044487

Variant names:

• chr10-87965537-T-C
• rs1044487
• NM_000314.8:c.*65T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000314.8(PTEN):​c.*65T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00000696 in 143,604 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000070 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80
• Publications: 2 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.*65T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.*65T>C		3_prime_UTR_variant	Exon 10 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.*65T>C		3_prime_UTR_variant	Exon 9 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.*65T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.00000696 AC: 1 AN: 143604 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000241 AC: 1 AN: 414308 Hom.: 0 Cov.: 9 AF XY: 0.00000491 AC XY: 1 AN XY: 203670

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 8692

American (AMR) AF: 0.00 AC: 0 AN: 9540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6024

East Asian (EAS) AF: 0.00 AC: 0 AN: 9906

South Asian (SAS) AF: 0.00 AC: 0 AN: 20094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2322

European-Non Finnish (NFE) AF: 0.00000307 AC: 1 AN: 326182

Other (OTH) AF: 0.00 AC: 0 AN: 16060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000696 AC: 1 AN: 143604 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 1 AN XY: 69694

African (AFR) AF: 0.00 AC: 0 AN: 39462

American (AMR) AF: 0.00 AC: 0 AN: 14384

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3354

East Asian (EAS) AF: 0.00 AC: 0 AN: 5038

South Asian (SAS) AF: 0.00 AC: 0 AN: 4550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64996

Other (OTH) AF: 0.00 AC: 0 AN: 1942

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		4.8

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: rs1044487; hg19: chr10-89725294;