10-87863566-G-T

Variant names:

• chr10-87863566-G-T
• rs1044322
• ENST00000692337.1:c.8G>T

Variant summary

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

The ENST00000692337.1(MLDHR):​c.8G>T​(p.Arg3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000852 in 234,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: MLDHR ENST00000692337.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.84
• Publications: 10 publications found

Genes affected

MLDHR (HGNC:55481):

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]

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

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=-0.34).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692337.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLDHR	NM_001433720.1		c.8G>T	p.Arg3Leu	missense	Exon 1 of 1	NP_001420649.1
	PTEN	NM_000314.8	MANE Select	c.-904G>T		upstream_gene	N/A	NP_000305.3
	KLLN	NM_001126049.2	MANE Select	c.-1079C>A		upstream_gene	N/A	NP_001119521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLDHR	ENST00000692337.1		c.8G>T	p.Arg3Leu	missense	Exon 1 of 1	ENSP00000509326.1
	PTEN	ENST00000693560.1		c.-384G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000509861.1
	PTEN	ENST00000693560.1		c.-384G>T		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000852 AC: 2 AN: 234838 Hom.: 0 Cov.: 0 AF XY: 0.0000168 AC XY: 2 AN XY: 119374

African (AFR) AF: 0.00 AC: 0 AN: 6630

American (AMR) AF: 0.00 AC: 0 AN: 6982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8634

East Asian (EAS) AF: 0.00 AC: 0 AN: 22278

South Asian (SAS) AF: 0.00 AC: 0 AN: 2782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1224

European-Non Finnish (NFE) AF: 0.0000133 AC: 2 AN: 150286

Other (OTH) AF: 0.00 AC: 0 AN: 15422

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 13

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.94
PhyloP100		1.8
PromoterAI		-0.0064	Neutral
Mutation Taster		=298/2	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

Other links and lift over

dbSNP: rs1044322; hg19: chr10-89623323;