20-45313571-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_014276.4(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 NM_014276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.75

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 Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJL	NM_014276.4	c.723T>G	p.Ser241Arg	missense_variant	7/12	ENST00000343694.8
RBPJL	NM_001281449.2	c.723T>G	p.Ser241Arg	missense_variant	7/12
RBPJL	NM_001281448.2	c.723T>G	p.Ser241Arg	missense_variant	7/12
RBPJL	XM_011528522.3	c.723T>G	p.Ser241Arg	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJL	ENST00000343694.8	c.723T>G	p.Ser241Arg	missense_variant	7/12	1	NM_014276.4	A1
RBPJL	ENST00000372743.5	c.723T>G	p.Ser241Arg	missense_variant	7/12	1		P4
RBPJL	ENST00000372741.7	c.723T>G	p.Ser241Arg	missense_variant	7/12	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460972 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726678

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.: 32

Alfa AF: 0.0000843 Hom.: 0

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

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	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
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	D
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

Other links and lift over

dbSNP: rs923249010; hg19: chr20-43942211;