15-51951888-T-C

Position:

• chr15-51951888-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138792.4(LEO1):​c.1567A>G​(p.Met523Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,660 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LEO1 NM_138792.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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]

ACMG classification

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=0.20727077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEO1	NM_138792.4	c.1567A>G	p.Met523Val	missense_variant	9/12	ENST00000299601.10	NP_620147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEO1	ENST00000299601.10	c.1567A>G	p.Met523Val	missense_variant	9/12	1	NM_138792.4	ENSP00000299601	P1
LEO1	ENST00000315141.5	c.1387A>G	p.Met463Val	missense_variant	7/10	2		ENSP00000314610

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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

Jun 11, 2021

The c.1567A>G (p.M523V) alteration is located in exon 9 (coding exon 9) of the LEO1 gene. This alteration results from a A to G substitution at nucleotide position 1567, causing the methionine (M) at amino acid position 523 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.074
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.60	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.24
Sift	Benign	0.24	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.98	D;B
Vest4		0.47
MutPred		0.46		Loss of catalytic residue at M523 (P = 0.0801);.;
MVP		0.58
MPC		0.97
ClinPred		0.82	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.67

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

Other links and lift over

dbSNP: rs1436146941; hg19: chr15-52244085;