20-45314071-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014276.4(RBPJL):c.794G>A(p.Arg265Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000812 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029480755).
• BS2: High AC in GnomAd at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJL	NM_014276.4	c.794G>A	p.Arg265Gln	missense_variant	8/12	ENST00000343694.8
RBPJL	NM_001281449.2	c.794G>A	p.Arg265Gln	missense_variant	8/12
RBPJL	NM_001281448.2	c.794G>A	p.Arg265Gln	missense_variant	8/12
RBPJL	XM_011528522.3	c.794G>A	p.Arg265Gln	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJL	ENST00000343694.8	c.794G>A	p.Arg265Gln	missense_variant	8/12	1	NM_014276.4	A1
RBPJL	ENST00000372743.5	c.794G>A	p.Arg265Gln	missense_variant	8/12	1		P4
RBPJL	ENST00000372741.7	c.794G>A	p.Arg265Gln	missense_variant	8/12	1
RBPJL	ENST00000464504.2	c.38G>A	p.Arg13Gln	missense_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251372 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135886

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40 AN XY: 727236

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74374

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000833 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.794G>A (p.R265Q) alteration is located in exon 8 (coding exon 8) of the RBPJL gene. This alteration results from a G to A substitution at nucleotide position 794, causing the arginine (R) at amino acid position 265 to be replaced by a glutamine (Q). 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	Benign	0.066
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.081
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.089	T;T;T
Polyphen		0.057, 0.0010	.;B;B
Vest4		0.15
MVP		0.35
MPC		0.44
ClinPred		0.059	T
GERP RS		3.3
Varity_R		0.054
gMVP		0.17

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

Other links and lift over

dbSNP: rs150441483; hg19: chr20-43942711;