20-45309644-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014276.4(RBPJL):c.209G>A(p.Arg70Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,613,722 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (34 hom.)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.89

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011108696).
• BP6: Variant 20-45309644-G-A is Benign according to our data. Variant chr20-45309644-G-A is described in ClinVar as [Benign]. Clinvar id is 783865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0116 (1764/152310) while in subpopulation AFR AF= 0.0362 (1506/41558). AF 95% confidence interval is 0.0347. There are 28 homozygotes in gnomad4. There are 832 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1762 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJL	NM_014276.4	c.209G>A	p.Arg70Gln	missense_variant	3/12	ENST00000343694.8
RBPJL	NM_001281449.2	c.209G>A	p.Arg70Gln	missense_variant	3/12
RBPJL	NM_001281448.2	c.209G>A	p.Arg70Gln	missense_variant	3/12
RBPJL	XM_011528522.3	c.209G>A	p.Arg70Gln	missense_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJL	ENST00000343694.8	c.209G>A	p.Arg70Gln	missense_variant	3/12	1	NM_014276.4	A1
RBPJL	ENST00000372743.5	c.209G>A	p.Arg70Gln	missense_variant	3/12	1		P4
RBPJL	ENST00000372741.7	c.209G>A	p.Arg70Gln	missense_variant	3/12	1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1762 AN: 152192 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00490 AC: 1229 AN: 250770 Hom.: 13 AF XY: 0.00443 AC XY: 601 AN XY: 135538

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00586

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00259 AC: 3778 AN: 1461412 Hom.: 34 Cov.: 31 AF XY: 0.00268 AC XY: 1947 AN XY: 727014

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00613

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00494

GnomAD4 genome AF: 0.0116 AC: 1764 AN: 152310 Hom.: 28 Cov.: 32 AF XY: 0.0112 AC XY: 832 AN XY: 74486

Gnomad4 AFR AF: 0.0362

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00621 Hom.: 8

Bravo AF: 0.0130

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00558 AC: 678

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.29	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.076	T;T;T
Sift4G	Benign	0.067	T;T;T
Polyphen		0.88, 0.71	.;P;P
Vest4		0.35
MVP		0.60
MPC		0.52
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.084
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35032855; hg19: chr20-43938284;