chr15-51965799-T-C
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_138792.4(LEO1):āc.764A>Gā(p.Asp255Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00012 ( 1 hom., cov: 32)
Exomes š: 0.00011 ( 0 hom. )
Consequence
LEO1
NM_138792.4 missense
NM_138792.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 7.40
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0103392005).
BS2
High AC in GnomAd4 at 19 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LEO1 | NM_138792.4 | c.764A>G | p.Asp255Gly | missense_variant | 2/12 | ENST00000299601.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LEO1 | ENST00000299601.10 | c.764A>G | p.Asp255Gly | missense_variant | 2/12 | 1 | NM_138792.4 | P1 | |
LEO1 | ENST00000315141.5 | c.764A>G | p.Asp255Gly | missense_variant | 2/10 | 2 | |||
MAPK6 | ENST00000560802.1 | n.178+13516T>C | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152228Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000255 AC: 64AN: 251042Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135682
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GnomAD4 exome AF: 0.000115 AC: 168AN: 1461496Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 98AN XY: 727040
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152228Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2022 | The c.764A>G (p.D255G) alteration is located in exon 2 (coding exon 2) of the LEO1 gene. This alteration results from a A to G substitution at nucleotide position 764, causing the aspartic acid (D) at amino acid position 255 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at