10-87965536-CTT-CT

Variant names:

• chr10-87965536-CT-C
• rs878853930
• NM_000314.8:c.*75delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_000314.8(PTEN):​c.*75delT variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000949 in 144,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 31)
  • Exomes 𝑓: 0.10 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.80

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 10-87965536-CT-C is Benign according to our data. Variant chr10-87965536-CT-C is described in ClinVar as [Benign]. Clinvar id is 237636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000949 (137/144428) while in subpopulation AMR AF = 0.0011 (16/14480). AF 95% confidence interval is 0.000704. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.*75delT		3_prime_UTR_variant	Exon 9 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.*75delT		3_prime_UTR_variant	Exon 10 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.*75delT		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.*75delT		3_prime_UTR_variant	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.000935 AC: 135 AN: 144364 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000380

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000888

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00459

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000887

Gnomad OTH AF: 0.000512

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 85462 AN: 847976 Hom.: 0 Cov.: 9 AF XY: 0.102 AC XY: 42834 AN XY: 419460

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

African (AFR) AF: 0.106 AC: 1995 AN: 18776

American (AMR) AF: 0.132 AC: 3351 AN: 25296

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 1735 AN: 13976

East Asian (EAS) AF: 0.109 AC: 2291 AN: 21102

South Asian (SAS) AF: 0.117 AC: 5383 AN: 46092

European-Finnish (FIN) AF: 0.108 AC: 3157 AN: 29266

Middle Eastern (MID) AF: 0.0691 AC: 261 AN: 3778

European-Non Finnish (NFE) AF: 0.0970 AC: 63565 AN: 655426

Other (OTH) AF: 0.109 AC: 3724 AN: 34264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000949 AC: 137 AN: 144428 Hom.: 0 Cov.: 31 AF XY: 0.00115 AC XY: 81 AN XY: 70182

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

African (AFR) AF: 0.000404 AC: 16 AN: 39556

American (AMR) AF: 0.00110 AC: 16 AN: 14480

Ashkenazi Jewish (ASJ) AF: 0.000888 AC: 3 AN: 3378

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5018

South Asian (SAS) AF: 0.00 AC: 0 AN: 4528

European-Finnish (FIN) AF: 0.00459 AC: 41 AN: 8934

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.000887 AC: 58 AN: 65382

Other (OTH) AF: 0.000507 AC: 1 AN: 1972

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000216 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PTEN hamartoma tumor syndrome Benign:1

Jul 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=64/36	polymorphism

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

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Other links and lift over

dbSNP: rs878853930; hg19: chr10-89725293; COSMIC: COSV64303800; COSMIC: COSV64303800;