rs144873312

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_138792.4(LEO1):​c.893C>T​(p.Ala298Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,612,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A298A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

LEO1
NM_138792.4 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.20
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.019419521).
BP6
Variant 15-51962415-G-A is Benign according to our data. Variant chr15-51962415-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3537868.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LEO1NM_138792.4 linkc.893C>T p.Ala298Val missense_variant Exon 3 of 12 ENST00000299601.10 NP_620147.1 Q8WVC0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LEO1ENST00000299601.10 linkc.893C>T p.Ala298Val missense_variant Exon 3 of 12 1 NM_138792.4 ENSP00000299601.5 Q8WVC0-1
LEO1ENST00000315141.5 linkc.893C>T p.Ala298Val missense_variant Exon 3 of 10 2 ENSP00000314610.5 Q8WVC0-2
MAPK6ENST00000560802.1 linkn.178+10132G>A intron_variant Intron 1 of 2 4

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152146
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000518
AC:
13
AN:
251072
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135738
show subpopulations
Gnomad AFR exome
AF:
0.000554
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS 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:
0.0000404
AC:
59
AN:
1460426
Hom.:
0
Cov.:
29
AF XY:
0.0000413
AC XY:
30
AN XY:
726602
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152264
Hom.:
0
Cov.:
31
AF XY:
0.0000806
AC XY:
6
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000547
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.000456
AC:
2
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Jun 28, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
13
DANN
Benign
0.92
DEOGEN2
Benign
0.17
T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.0035
T
MetaRNN
Benign
0.019
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.55
N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.053
Sift
Benign
0.45
T;T
Sift4G
Benign
0.26
T;T
Polyphen
0.0
B;B
Vest4
0.14
MVP
0.17
MPC
0.78
ClinPred
0.0072
T
GERP RS
1.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.013
gMVP
0.057

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144873312; hg19: chr15-52254612; API