20-45314082-G-A

Position:

• chr20-45314082-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.805G>A​(p.Val269Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,614,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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=0.01323235).
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBPJL	NM_014276.4	c.805G>A	p.Val269Ile	missense_variant	8/12	ENST00000343694.8	NP_055091.2
RBPJL	NM_001281449.2	c.805G>A	p.Val269Ile	missense_variant	8/12		NP_001268378.1
RBPJL	NM_001281448.2	c.805G>A	p.Val269Ile	missense_variant	8/12		NP_001268377.1
RBPJL	XM_011528522.3	c.805G>A	p.Val269Ile	missense_variant	8/12		XP_011526824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJL	ENST00000343694.8	c.805G>A	p.Val269Ile	missense_variant	8/12	1	NM_014276.4	ENSP00000341243	A1
RBPJL	ENST00000372743.5	c.805G>A	p.Val269Ile	missense_variant	8/12	1		ENSP00000361828	P4
RBPJL	ENST00000372741.7	c.805G>A	p.Val269Ile	missense_variant	8/12	1		ENSP00000361826
RBPJL	ENST00000464504.2	c.49G>A	p.Val17Ile	missense_variant	1/5	3		ENSP00000483978

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251378 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727232

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74508

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

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

Jul 11, 2023

The c.805G>A (p.V269I) 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 805, causing the valine (V) at amino acid position 269 to be replaced by an isoleucine (I). 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	-0.48	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.15
DEOGEN2	Benign	0.049	.;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N;.;N
MutationTaster	Benign	0.81	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.40	N;N;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0080, 0.0010	.;B;B
Vest4		0.058
MVP		0.030
MPC		0.31
ClinPred		0.010	T
GERP RS		3.3
Varity_R		0.017
gMVP		0.072

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: rs568551533; hg19: chr20-43942722;