rs367614131

Variant names:

• chr15-51949945-C-T
• rs367614131
• NM_138792.4:c.1661G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138792.4(LEO1):​c.1661G>A​(p.Arg554His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LEO1 NM_138792.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• Publications: 1 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]

LEO1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1661G>A	p.Arg554His	missense	Exon 10 of 12	NP_620147.1	Q8WVC0-1
	LEO1	NM_001323903.2		c.1661G>A	p.Arg554His	missense	Exon 10 of 13	NP_001310832.1
	LEO1	NM_001426597.1		c.1661G>A	p.Arg554His	missense	Exon 10 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.1661G>A	p.Arg554His	missense	Exon 10 of 12	ENSP00000299601.5	Q8WVC0-1
	LEO1	ENST00000924051.1		c.1556G>A	p.Arg519His	missense	Exon 9 of 11	ENSP00000594110.1
	LEO1	ENST00000315141.5	TSL:2	c.1481G>A	p.Arg494His	missense	Exon 8 of 10	ENSP00000314610.5	Q8WVC0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251326 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

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	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.62
MPC		2.0
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.69

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

Other links and lift over

dbSNP: rs367614131; hg19: chr15-52242142;