15-51965755-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138792.4(LEO1):c.808A>G(p.Lys270Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

LEO1
NM_138792.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39

Variant links:

Genes affected

LEO1 (HGNC:30401): (LEO1 homolog, Paf1/RNA polymerase II complex component) LEO1, parafibromin (CDC73; MIM 607393), CTR9 (MIM 609366), and PAF1 (MIM 610506) form the PAF protein complex that associates with the RNA polymerase II subunit POLR2A (MIM 180660) and with a histone methyltransferase complex (Rozenblatt-Rosen et al., 2005 [PubMed 15632063]).[supplied by OMIM, Mar 2008]

LEO1 links:

MAPK6 (HGNC:6879): (mitogen-activated protein kinase 6) The protein encoded by this gene is a member of the Ser/Thr protein kinase family, and is most closely related to mitogen-activated protein kinases (MAP kinases). MAP kinases also known as extracellular signal-regulated kinases (ERKs), are activated through protein phosphorylation cascades and act as integration points for multiple biochemical signals. This kinase is localized in the nucleus, and has been reported to be activated in fibroblasts upon treatment with serum or phorbol esters. [provided by RefSeq, Jul 2008]

MAPK6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.185539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEO1	NM_138792.4 linkuse as main transcript	c.808A>G	p.Lys270Glu	missense_variant	2/12	ENST00000299601.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEO1	ENST00000299601.10 linkuse as main transcript	c.808A>G	p.Lys270Glu	missense_variant	2/12	1	NM_138792.4	P1	Q8WVC0-1
LEO1	ENST00000315141.5 linkuse as main transcript	c.808A>G	p.Lys270Glu	missense_variant	2/10	2			Q8WVC0-2
MAPK6	ENST00000560802.1 linkuse as main transcript	n.178+13472T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000820

AC:

AN:

243780

Hom.:

AF XY:

0.00000759

AC XY:

AN XY:

131806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000612

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1451730

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721570

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000703

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.808A>G (p.K270E) alteration is located in exon 2 (coding exon 2) of the LEO1 gene. This alteration results from a A to G substitution at nucleotide position 808, causing the lysine (K) at amino acid position 270 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0041

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.81

L;L

MutationTaster

Benign

0.92

D;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.058

Sift

Benign

0.10

T;D

Sift4G

Benign

0.53

T;T

Polyphen

0.95

P;B

Vest4

0.49

MutPred

0.25

Loss of ubiquitination at K270 (P = 0.0107);Loss of ubiquitination at K270 (P = 0.0107);

MVP

0.36

MPC

1.1

ClinPred

0.17

GERP RS

5.4

Varity_R

0.098

gMVP

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over