20-45312312-G-C

Position:

• chr20-45312312-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014276.4(RBPJL):​c.536G>C​(p.Arg179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12360802).
• BS2: High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBPJL	NM_014276.4	c.536G>C	p.Arg179Pro	missense_variant	6/12	ENST00000343694.8	NP_055091.2
RBPJL	NM_001281449.2	c.536G>C	p.Arg179Pro	missense_variant	6/12		NP_001268378.1
RBPJL	NM_001281448.2	c.536G>C	p.Arg179Pro	missense_variant	6/12		NP_001268377.1
RBPJL	XM_011528522.3	c.536G>C	p.Arg179Pro	missense_variant	6/12		XP_011526824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJL	ENST00000343694.8	c.536G>C	p.Arg179Pro	missense_variant	6/12	1	NM_014276.4	ENSP00000341243	A1
RBPJL	ENST00000372743.5	c.536G>C	p.Arg179Pro	missense_variant	6/12	1		ENSP00000361828	P4
RBPJL	ENST00000372741.7	c.536G>C	p.Arg179Pro	missense_variant	6/12	1		ENSP00000361826

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000426

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000258 AC: 64 AN: 248260 Hom.: 0 AF XY: 0.000282 AC XY: 38 AN XY: 134524

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000366 AC: 535 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 254 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74506

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

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

Jun 18, 2021

The c.536G>C (p.R179P) alteration is located in exon 6 (coding exon 6) of the RBPJL gene. This alteration results from a G to C substitution at nucleotide position 536, causing the arginine (R) at amino acid position 179 to be replaced by a proline (P). 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	0.30
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	0.96	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.083	T;D;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.74, 0.52	.;P;P
Vest4		0.46
MVP		0.63
MPC		1.2
ClinPred		0.096	T
GERP RS		0.60
Varity_R		0.29
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149866429; hg19: chr20-43940952;