NM_138792.4:c.1936G>A

Variant names:

• chr15-51938221-C-T
• NM_138792.4:c.1936G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138792.4(LEO1):​c.1936G>A​(p.Asp646Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LEO1 NM_138792.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.97
• 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]

TMOD3 (HGNC:11873): (tropomodulin 3) Enables cadherin binding activity involved in cell-cell adhesion. Predicted to be involved in actin filament organization; muscle contraction; and myofibril assembly. Predicted to act upstream of or within actin cytoskeleton organization; erythrocyte development; and positive regulation of mitotic cell cycle phase transition. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

LOC112268148 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23123637).

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.1936G>A	p.Asp646Asn	missense	Exon 12 of 12	NP_620147.1	Q8WVC0-1
	LEO1	NM_001323903.2		c.2034G>A	p.Met678Ile	missense	Exon 13 of 13	NP_001310832.1
	LEO1	NM_001323904.2		c.1932G>A	p.Met644Ile	missense	Exon 12 of 12	NP_001310833.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEO1	ENST00000299601.10	TSL:1 MANE Select	c.1936G>A	p.Asp646Asn	missense	Exon 12 of 12	ENSP00000299601.5	Q8WVC0-1
	LEO1	ENST00000924051.1		c.1831G>A	p.Asp611Asn	missense	Exon 11 of 11	ENSP00000594110.1
	LEO1	ENST00000315141.5	TSL:2	c.1756G>A	p.Asp586Asn	missense	Exon 10 of 10	ENSP00000314610.5	Q8WVC0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457648 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725232

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109548

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 33

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	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.083
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.36	T
Polyphen		0.94	P
Vest4		0.27
MutPred		0.13		Gain of MoRF binding (P = 0.0331)
MVP		0.60
MPC		1.7
ClinPred		0.93	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.041

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

hg19: chr15-52230418;