15-51962485-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_138792.4(LEO1):c.823A>G(p.Arg275Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,608,100 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (44 hom.)
• Consequence: LEO1 NM_138792.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.40

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051706433).
• BP6: Variant 15-51962485-T-C is Benign according to our data. Variant chr15-51962485-T-C is described in ClinVar as [Benign]. Clinvar id is 3060993.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0055 (838/152368) while in subpopulation EAS AF= 0.0305 (158/5188). AF 95% confidence interval is 0.0266. There are 9 homozygotes in gnomad4. There are 541 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 837 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEO1	NM_138792.4	c.823A>G	p.Arg275Gly	missense_variant	3/12	ENST00000299601.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEO1	ENST00000299601.10	c.823A>G	p.Arg275Gly	missense_variant	3/12	1	NM_138792.4	P1
LEO1	ENST00000315141.5	c.823A>G	p.Arg275Gly	missense_variant	3/10	2
MAPK6	ENST00000560802.1	n.178+10202T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152250 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00950 AC: 2377 AN: 250196 Hom.: 33 AF XY: 0.00780 AC XY: 1054 AN XY: 135206

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0344

Gnomad SAS exome AF: 0.000826

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00639

GnomAD4 exome AF: 0.00287 AC: 4179 AN: 1455732 Hom.: 44 Cov.: 28 AF XY: 0.00270 AC XY: 1958 AN XY: 724540

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0251

Gnomad4 SAS exome AF: 0.000989

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.000392

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152368 Hom.: 9 Cov.: 31 AF XY: 0.00726 AC XY: 541 AN XY: 74518

Gnomad4 AFR AF: 0.000817

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0305

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00199 Hom.: 4

Bravo AF: 0.00504

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00754 AC: 916

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LEO1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2020

This variant is classified as 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	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.063
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.89	D;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.65	P;P
Vest4		0.39
MVP		0.33
MPC		1.4
ClinPred		0.019	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.041

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs116808659; hg19: chr15-52254682;