20-45309644-G-A

Position:

chr20-45309644-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000343694.8(RBPJL):c.209G>A(p.Arg70Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,613,722 control chromosomes in the GnomAD database, including 62 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 34 hom. )

Consequence

RBPJL
ENST00000343694.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.89

Variant links:

Genes affected

RBPJL (HGNC:13761): (recombination signal binding protein for immunoglobulin kappa J region like) This gene encodes a member of the suppressor of hairless protein family. A similar protein in mouse is a transcription factor that binds to DNA sequences almost identical to that bound by the Notch receptor signaling pathway transcription factor recombining binding protein J. The mouse protein has been shown to activate transcription in concert with Epstein-Barr virus nuclear antigen-2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RBPJL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011108696).

BP6

Variant 20-45309644-G-A is Benign according to our data. Variant chr20-45309644-G-A is described in ClinVar as [Benign]. Clinvar id is 783865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1764/152310) while in subpopulation AFR AF= 0.0362 (1506/41558). AF 95% confidence interval is 0.0347. There are 28 homozygotes in gnomad4. There are 832 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1764 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RBPJL	NM_014276.4 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12	ENST00000343694.8	NP_055091.2
RBPJL	NM_001281449.2 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12		NP_001268378.1
RBPJL	NM_001281448.2 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12		NP_001268377.1
RBPJL	XM_011528522.3 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12		XP_011526824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJL	ENST00000343694.8 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12	1	NM_014276.4	ENSP00000341243	A1	Q9UBG7-1
RBPJL	ENST00000372743.5 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12	1		ENSP00000361828	P4	Q9UBG7-2
RBPJL	ENST00000372741.7 linkuse as main transcript	c.209G>A	p.Arg70Gln	missense_variant	3/12	1		ENSP00000361826

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1762

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00490

AC:

1229

AN:

250770

Hom.:

AF XY:

0.00443

AC XY:

601

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.0361

Gnomad AMR exome

AF:

0.00343

Gnomad ASJ exome

AF:

0.00884

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00586

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00524

GnomAD4 exome

AF:

0.00259

AC:

3778

AN:

1461412

Hom.:

Cov.:

AF XY:

0.00268

AC XY:

1947

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0347

Gnomad4 AMR exome

AF:

0.00392

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00613

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.00494

GnomAD4 genome

AF:

0.0116

AC:

1764

AN:

152310

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0362

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00621

Hom.:

Bravo

AF:

0.0130

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0374

AC:

165

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00558

AC:

678

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;T;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.5

L;.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.29

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.076

T;T;T

Sift4G

Benign

0.067

T;T;T

Polyphen

0.88, 0.71

.;P;P

Vest4

0.35

MVP

0.60

MPC

0.52

ClinPred

0.018

GERP RS

5.5

Varity_R

0.084

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over