chr15-51938168-T-A

Position:

• chr15-51938168-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138792.4(LEO1):​c.1989A>T​(p.Glu663Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,560,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: LEO1 NM_138792.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.46

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]

LOC112268148 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017872155).
• BP6: Variant 15-51938168-T-A is Benign according to our data. Variant chr15-51938168-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 3042939.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEO1	NM_138792.4	c.1989A>T	p.Glu663Asp	missense_variant	12/12	ENST00000299601.10	NP_620147.1
LOC112268148	XR_007064635.1	n.2581+3814T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEO1	ENST00000299601.10	c.1989A>T	p.Glu663Asp	missense_variant	12/12	1	NM_138792.4	ENSP00000299601	P1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00981

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000582 AC: 144 AN: 247214 Hom.: 0 AF XY: 0.000561 AC XY: 75 AN XY: 133588

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00669

Gnomad SAS exome AF: 0.000237

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000713

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000291 AC: 410 AN: 1408360 Hom.: 1 Cov.: 23 AF XY: 0.000288 AC XY: 203 AN XY: 703744

Gnomad4 AFR exome AF: 0.000802

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00723

Gnomad4 SAS exome AF: 0.000285

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000366

Gnomad4 OTH exome AF: 0.000529

GnomAD4 genome AF: 0.000564 AC: 86 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74520

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00983

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000465 Hom.: 1

Bravo AF: 0.000578

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.000165

EpiControl AF: 0.0000598

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

LEO1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.67	T;T
Polyphen		0.018	B;B
Vest4		0.15
MutPred		0.075		Loss of stability (P = 0.1508);.;
MVP		0.35
MPC		0.71
ClinPred		0.050	T
GERP RS		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.23
gMVP		0.012

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: rs114649602; hg19: chr15-52230365;