rs2056963190

Variant names:

• chr15-51953258-G-A
• rs2056963190
• NM_138792.4:c.1346C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 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. 12/21 in silico tools predict a damaging 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
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138792.4. 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
	LEO1	NM_138792.4	MANE Select	c.1346C>T	p.Ser449Phe	missense	Exon 8 of 12	NP_620147.1	Q8WVC0-1
	LEO1	NM_001323903.2		c.1346C>T	p.Ser449Phe	missense	Exon 8 of 13	NP_001310832.1
	LEO1	NM_001426597.1		c.1346C>T	p.Ser449Phe	missense	Exon 8 of 12	NP_001413526.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEO1	ENST00000299601.10	TSL:1 MANE Select	c.1346C>T	p.Ser449Phe	missense	Exon 8 of 12	ENSP00000299601.5	Q8WVC0-1
	LEO1	ENST00000924051.1		c.1241C>T	p.Ser414Phe	missense	Exon 7 of 11	ENSP00000594110.1
	LEO1	ENST00000315141.5	TSL:2	c.1166C>T	p.Ser389Phe	missense	Exon 6 of 10	ENSP00000314610.5	Q8WVC0-2

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	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

Other links and lift over

dbSNP: rs2056963190; hg19: chr15-52245455;