rs587780001

chr10-87863494-G-Achr10-87863494-G-Cchr10-87863494-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001126049.2(KLLN):c.-1007C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 383,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: KLLN NM_001126049.2 5_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: -0.131

Genes affected

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]

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-87863494-G-A is Benign according to our data. Variant chr10-87863494-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127684.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87863494-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLLN	NM_001126049.2	c.-1007C>T		5_prime_UTR_variant	1/1	ENST00000445946.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLLN	ENST00000445946.5	c.-1007C>T		5_prime_UTR_variant	1/1		NM_001126049.2	P1
PTEN	ENST00000693560.1	c.-456G>A		5_prime_UTR_variant	1/10
PTEN	ENST00000688308.1	c.-17+381G>A		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.000914 AC: 139 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000493 AC: 114 AN: 231298 Hom.: 0 Cov.: 0 AF XY: 0.000569 AC XY: 67 AN XY: 117714

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.000879

Gnomad4 ASJ exome AF: 0.00270

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74452

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00189

Bravo AF: 0.00118

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PTEN: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2017	This variant is associated with the following publications: (PMID: 25669429) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The PTEN c.-975G>A (also known as c.-976G>A) variant involves the alteration of a non-conserved nucleotide located in the promoter region of PTEN. One in silico tool predicts a benign outcome for this variant. This variant was found in 20/30846 control chromosomes (gnomAD) at a frequency of 0.0006484, which is approximately 104 times the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this variant is likely a benign polymorphism. A publication, Nizialek_2015, cites the variant to have been found in their cohort, however, it is unclear as to whether the variant was found in affected individuals or controls. Although the authors do report another variant at this position, c.-976G>C that segregated with CS in the family and was observed to have promoter methylation, although methylation is commonly associated with C residues. A clinical diagnostic laboratory cites the variant as "uncertain significance." In addition, an internal LCA sample reports the variant to co-occur with a likely pathogenic TP53 variant, c.375+2T>C. Therefore, the variant of interest has been classified as Benign. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2019

- -

PTEN hamartoma tumor syndrome Benign:1

Likely benign, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Nov 22, 2019

PTEN c.-975G>A (NC_000010.10:g.89623251G>A) meets criteria to be classified as likely benign 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). BS1: Allele frequency of 0.00127 (0.127%, 11/8660 alleles) in the African subpopulation of the gnomAD cohort. (PMID 27535533) BS2_P: Meets criteria for BS2 (observed in the homozygous state in at least one healthy or PHTS-unaffected individual) but BS1 is also applied. (internal laboratory contributor ClinVar Organization ID: 61756) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Sep 29, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	11
Dann	Benign	0.91

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

LitVar

Other links and lift over

dbSNP: rs587780001; hg19: chr10-89623251;