15-51953258-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138792.4(LEO1):c.1346C>T(p.Ser449Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LEO1 NM_138792.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

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]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEO1	NM_138792.4	c.1346C>T	p.Ser449Phe	missense_variant	8/12	ENST00000299601.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEO1	ENST00000299601.10	c.1346C>T	p.Ser449Phe	missense_variant	8/12	1	NM_138792.4	P1
LEO1	ENST00000315141.5	c.1166C>T	p.Ser389Phe	missense_variant	6/10	2
LEO1	ENST00000558949.1	n.587C>T		non_coding_transcript_exon_variant	2/2	3
MAPK6	ENST00000560802.1	n.178+975G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.1346C>T (p.S449F) alteration is located in exon 8 (coding exon 8) of the LEO1 gene. This alteration results from a C to T substitution at nucleotide position 1346, causing the serine (S) at amino acid position 449 to be replaced by a phenylalanine (F). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.86		Loss of disorder (P = 0.0315);.;
MVP		0.83
MPC		2.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.93
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs2056963190; hg19: chr15-52245455;