ENST00000692337.1:c.55C>T

Variant names:

• chr10-87863613-C-T
• rs587779996
• ENST00000692337.1:c.55C>T
• MLDHR p.Arg19*

Variant summary

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

The ENST00000692337.1(MLDHR):​c.55C>T​(p.Arg19*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000084 in 238,080 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 (★). Synonymous variant affecting the same amino acid position (i.e. R19R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: MLDHR ENST00000692337.1 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0900
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLDHR	NM_001433720.1		c.55C>T	p.Arg19*	stop_gained	Exon 1 of 1	NP_001420649.1	C0HLV8
	PTEN	NM_000314.8	MANE Select	c.-857C>T		upstream_gene	N/A	NP_000305.3
	KLLN	NM_001126049.2	MANE Select	c.-1126G>A		upstream_gene	N/A	NP_001119521.1	B2CW77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLDHR	ENST00000692337.1		c.55C>T	p.Arg19*	stop_gained	Exon 1 of 1	ENSP00000509326.1	C0HLV8
	PTEN	ENST00000693560.1		c.-337C>T		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000688308.1		c.-17+500C>T		intron	N/A	ENSP00000508752.1	P60484-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000840 AC: 2 AN: 238080 Hom.: 0 Cov.: 0 AF XY: 0.0000165 AC XY: 2 AN XY: 120996

African (AFR) AF: 0.00 AC: 0 AN: 6742

American (AMR) AF: 0.00 AC: 0 AN: 7130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8786

East Asian (EAS) AF: 0.00 AC: 0 AN: 22480

South Asian (SAS) AF: 0.00 AC: 0 AN: 2964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1250

European-Non Finnish (NFE) AF: 0.0000131 AC: 2 AN: 152358

Other (OTH) AF: 0.00 AC: 0 AN: 15702

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	36
DANN	Benign	0.94
PhyloP100		0.090
PromoterAI		0.10	Neutral
Mutation Taster		=297/3	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587779996;

hg19: chr10-89623370;