15-51954547-C-G

Variant names:

• chr15-51954547-C-G
• rs750538875
• NM_138792.4:c.1274G>C

Variant summary

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

The NM_138792.4(LEO1):​c.1274G>C​(p.Arg425Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • 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: 5.16
• 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: 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.1274G>C	p.Arg425Pro	missense	Exon 7 of 12	NP_620147.1	Q8WVC0-1
	LEO1	NM_001323903.2		c.1274G>C	p.Arg425Pro	missense	Exon 7 of 13	NP_001310832.1
	LEO1	NM_001426597.1		c.1274G>C	p.Arg425Pro	missense	Exon 7 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.1274G>C	p.Arg425Pro	missense	Exon 7 of 12	ENSP00000299601.5	Q8WVC0-1
	LEO1	ENST00000924051.1		c.1169G>C	p.Arg390Pro	missense	Exon 6 of 11	ENSP00000594110.1
	LEO1	ENST00000971766.1		c.518G>C	p.Arg173Pro	missense	Exon 6 of 11	ENSP00000641825.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460326 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726608

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110696

Other (OTH) AF: 0.00 AC: 0 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

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	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0051	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.91	P
Vest4		0.72
MutPred		0.58		Loss of MoRF binding (P = 0.0045)
MVP		0.55
MPC		2.1
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs750538875; hg19: chr15-52246744;