10-87863560-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The ENST00000692337.1(MLDHR):c.2T>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000156 in 383,466 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

MLDHR
ENST00000692337.1 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.25

Publications

2 publications found

Variant links:

Genes affected

MLDHR (HGNC:55481):

MLDHR links:

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 links:

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]

KLLN Gene-Disease associations (from GenCC):

Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 4
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

KLLN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.-910T>G		upstream_gene_variant		ENST00000371953.8	NP_000305.3
KLLN	NM_001126049.2 link	c.-1073A>C		upstream_gene_variant		ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MLDHR	ENST00000692337.1 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 1			ENSP00000509326.1
PTEN	ENST00000371953.8 link	c.-910T>G		upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3
KLLN	ENST00000445946.5 link	c.-1073A>C		upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000216

AC:

AN:

231838

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

117842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6532

American (AMR)

AF:

0.00

AC:

AN:

6876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8514

East Asian (EAS)

AF:

0.000136

AC:

AN:

22106

South Asian (SAS)

AF:

0.00

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1226

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

148302

Other (OTH)

AF:

0.00

AC:

AN:

15218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74052

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41308

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67872

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PTEN c.-910T>G is located in the untranscribed region upstream of the PTEN gene region. The variant was absent in 31172 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-910T>G has been reported in the literature in individuals affected with Familial adenomatous polyposis, however this patient also carried a pathogenic APC variant (Kim_2019). This report does not provide unequivocal conclusions about association of the variant with Cowden Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31269945). ClinVar contains an entry for this variant (Variation ID: 488768). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Oct 31, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted PTEN c.-910T>G, and describes a nucleotide substitution 910 base pairs upstream of the ATG translational start site in the PTEN promoter region. The surrounding sequence, with the base that is substituted in brackets, is GTGA[T/G]GTGG. This variant, also called c.-909T>G using alternate numbering, has not been published in the literature to our knowledge. Variants within the PTEN promoter have been observed in individuals with features of Cowden syndrome (Zhou 2003). Based on currently available information, it is unclear whether PTEN c.-910T>G is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

4.2

PromoterAI

-0.20

Neutral

(source)

Mutation Taster

=290/10

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over