20-45309619-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014276.4(RBPJL):c.184C>A(p.Gln62Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14006305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJL	NM_014276.4	c.184C>A	p.Gln62Lys	missense_variant	3/12	ENST00000343694.8
RBPJL	NM_001281449.2	c.184C>A	p.Gln62Lys	missense_variant	3/12
RBPJL	NM_001281448.2	c.184C>A	p.Gln62Lys	missense_variant	3/12
RBPJL	XM_011528522.3	c.184C>A	p.Gln62Lys	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJL	ENST00000343694.8	c.184C>A	p.Gln62Lys	missense_variant	3/12	1	NM_014276.4	A1
RBPJL	ENST00000372743.5	c.184C>A	p.Gln62Lys	missense_variant	3/12	1		P4
RBPJL	ENST00000372741.7	c.184C>A	p.Gln62Lys	missense_variant	3/12	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 24, 2024

The c.184C>A (p.Q62K) alteration is located in exon 3 (coding exon 3) of the RBPJL gene. This alteration results from a C to A substitution at nucleotide position 184, causing the glutamine (Q) at amino acid position 62 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Benign	0.82
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.52	N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.0010	.;B;B
Vest4		0.38
MutPred		0.34		Gain of methylation at Q62 (P = 0.0038);Gain of methylation at Q62 (P = 0.0038);Gain of methylation at Q62 (P = 0.0038);
MVP		0.64
MPC		0.52
ClinPred		0.18	T
GERP RS		4.6
Varity_R		0.084
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43938259;