10-87960876-CTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr10-87960876-C-CTTTT
• rs34003473
• NM_000314.8:c.802-6_802-3dupTTTT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 6P and 12B. PVS1_Strong PM2 BP6_Very_Strong BS1

The NM_000314.8(PTEN):​c.802-6_802-3dupTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000702 in 1,425,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37

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 Likely_benign. Variant got -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18564357 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: ttttttttttttttttttAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-87960876-C-CTTTT is Benign according to our data. Variant chr10-87960876-C-CTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 3075885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000248 (31/125124) while in subpopulation AFR AF= 0.000975 (31/31790). AF 95% confidence interval is 0.000705. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.802-6_802-3dupTTTT		splice_acceptor_variant, intron_variant	Intron 7 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-6_1321-3dupTTTT		splice_acceptor_variant, intron_variant	Intron 8 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.211-6_211-3dupTTTT		splice_acceptor_variant, intron_variant	Intron 7 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-18_802-17insTTTT		intron_variant	Intron 7 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 30 AN: 125128 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000945

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000531 AC: 69 AN: 1299994 Hom.: 0 Cov.: 0 AF XY: 0.0000494 AC XY: 32 AN XY: 647278

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000153

Gnomad4 ASJ exome AF: 0.0000426

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000140

Gnomad4 FIN exome AF: 0.0000214

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.000112

GnomAD4 genome AF: 0.000248 AC: 31 AN: 125124 Hom.: 0 Cov.: 26 AF XY: 0.000199 AC XY: 12 AN XY: 60428

Gnomad4 AFR AF: 0.000975

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802-3_802-2insTTTT variant in PTEN is classified as benign because it has not been reported in individuals with disease, is located in the 3' splice region but computational tools do not predict a splicing impact and affects a multiallelic stretch of Ts. ACMG/AMP criteria applied: BA1 -

Hereditary cancer-predisposing syndrome Benign:1

Sep 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34003473; hg19: chr10-89720633;