10-87863560-T-G

Variant names:

• chr10-87863560-T-G
• rs550385924
• ENST00000692337.1:c.2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1 PM2 BP6

The NM_001433720.1(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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MLDHR NM_001433720.1 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.25
• Publications: 2 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-87863560-T-G is Benign according to our data. Variant chr10-87863560-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488768.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001433720.1. 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.2T>G	p.Met1?	start_lost	Exon 1 of 1	NP_001420649.1	C0HLV8
	PTEN	NM_000314.8	MANE Select	c.-910T>G		upstream_gene	N/A	NP_000305.3
	KLLN	NM_001126049.2	MANE Select	c.-1073A>C		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.2T>G	p.Met1?	start_lost	Exon 1 of 1	ENSP00000509326.1	C0HLV8
	PTEN	ENST00000693560.1		c.-390T>G		5_prime_UTR	Exon 1 of 10	ENSP00000509861.1	A0A8I5KSF9
	PTEN	ENST00000688308.1		c.-17+447T>G		intron	N/A	ENSP00000508752.1	P60484-1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151628 Hom.: 0 Cov.: 32

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: 5 AN: 231838 Hom.: 0 Cov.: 0 AF XY: 0.0000255 AC XY: 3 AN XY: 117842

African (AFR) AF: 0.00 AC: 0 AN: 6532

American (AMR) AF: 0.00 AC: 0 AN: 6876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8514

East Asian (EAS) AF: 0.000136 AC: 3 AN: 22106

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1226

European-Non Finnish (NFE) AF: 0.0000135 AC: 2 AN: 148302

Other (OTH) AF: 0.00 AC: 0 AN: 15218

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151628 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74052

African (AFR) AF: 0.0000242 AC: 1 AN: 41308

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.88
PhyloP100		4.2
PromoterAI		-0.20	Neutral
Mutation Taster		=290/10	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: rs550385924; hg19: chr10-89623317;