20-45313557-G-A

Variant summary

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

The NM_014276.4(RBPJL):c.709G>A(p.Ala237Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

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=0.11340192).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJL	NM_014276.4	c.709G>A	p.Ala237Thr	missense_variant	7/12	ENST00000343694.8
RBPJL	NM_001281449.2	c.709G>A	p.Ala237Thr	missense_variant	7/12
RBPJL	NM_001281448.2	c.709G>A	p.Ala237Thr	missense_variant	7/12
RBPJL	XM_011528522.3	c.709G>A	p.Ala237Thr	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJL	ENST00000343694.8	c.709G>A	p.Ala237Thr	missense_variant	7/12	1	NM_014276.4	A1
RBPJL	ENST00000372743.5	c.709G>A	p.Ala237Thr	missense_variant	7/12	1		P4
RBPJL	ENST00000372741.7	c.709G>A	p.Ala237Thr	missense_variant	7/12	1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250548 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135382

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461594 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727070

Gnomad4 AFR exome AF: 0.000299

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: 0.00000270

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74484

Gnomad4 AFR AF: 0.000337

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: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.000230

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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, 2023

The c.709G>A (p.A237T) alteration is located in exon 7 (coding exon 7) of the RBPJL gene. This alteration results from a G to A substitution at nucleotide position 709, causing the alanine (A) at amino acid position 237 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Benign	0.97
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.040	N;N;N
REVEL	Benign	0.097
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.13, 0.053	.;B;B
Vest4		0.32
MutPred		0.58		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.35
MPC		0.66
ClinPred		0.033	T
GERP RS		4.1
Varity_R		0.073
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs552843568; hg19: chr20-43942197; COSMIC: COSV104641897; COSMIC: COSV104641897;