Variant 20-45313571-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The ENST00000343694.8(RBPJL):c.723T>G(p.Ser241Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RBPJL
ENST00000343694.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.75

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RBPJL	NM_014276.4 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12	ENST00000343694.8	NP_055091.2
RBPJL	NM_001281449.2 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12		NP_001268378.1
RBPJL	NM_001281448.2 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12		NP_001268377.1
RBPJL	XM_011528522.3 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12		XP_011526824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJL	ENST00000343694.8 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12	1	NM_014276.4	ENSP00000341243	A1	Q9UBG7-1
RBPJL	ENST00000372743.5 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12	1		ENSP00000361828	P4	Q9UBG7-2
RBPJL	ENST00000372741.7 linkuse as main transcript	c.723T>G	p.Ser241Arg	missense_variant	7/12	1		ENSP00000361826

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000843

Hom.:

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

Nov 03, 2022

The c.723T>G (p.S241R) alteration is located in exon 7 (coding exon 7) of the RBPJL gene. This alteration results from a T to G substitution at nucleotide position 723, causing the serine (S) at amino acid position 241 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

L;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;T;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.89

MutPred

0.83

Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);

MVP

0.18

MPC

1.2

ClinPred

1.0

GERP RS

-6.4

Varity_R

0.90

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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