15-51953193-G-T

Variant names:

• chr15-51953193-G-T
• NM_138792.4:c.1411C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138792.4(LEO1):​c.1411C>A​(p.Leu471Ile) variant causes a missense change. 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: 4.81

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEO1	NM_138792.4	c.1411C>A	p.Leu471Ile	missense_variant	Exon 8 of 12	ENST00000299601.10	NP_620147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEO1	ENST00000299601.10	c.1411C>A	p.Leu471Ile	missense_variant	Exon 8 of 12	1	NM_138792.4	ENSP00000299601.5
LEO1	ENST00000315141.5	c.1231C>A	p.Leu411Ile	missense_variant	Exon 6 of 10	2		ENSP00000314610.5
MAPK6	ENST00000560802.1	n.178+910G>T		intron_variant	Intron 1 of 2	4
LEO1	ENST00000558949.1	n.*22C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 30, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.76		Loss of catalytic residue at L471 (P = 0.0629);.;
MVP		0.53
MPC		2.0
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.71
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-52245390;