4-26322296-G-C

Position:

• chr4-26322296-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015874.6(RBPJ):​c.20+1248G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 152,212 control chromosomes in the GnomAD database, including 816 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.091 (816 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: RBPJ NM_015874.6 intron
• Scores: Splicing: ADA: 0.00002193
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338

Genes affected

RBPJ (HGNC:5724): (recombination signal binding protein for immunoglobulin kappa J region) The protein encoded by this gene is a transcriptional regulator important in the Notch signaling pathway. The encoded protein acts as a repressor when not bound to Notch proteins and an activator when bound to Notch proteins. It is thought to function by recruiting chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins to Notch signaling pathway genes. Several transcript variants encoding different isoforms have been found for this gene, and several pseudogenes of this gene exist on chromosome 9. [provided by RefSeq, Oct 2013]

RBPJ (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBPJ	NM_015874.6	c.20+1248G>C		intron_variant		ENST00000355476.8	NP_056958.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJ	ENST00000355476.8	c.20+1248G>C		intron_variant		1	NM_015874.6	ENSP00000347659.4

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13857 AN: 152084 Hom.: 814 Cov.: 32

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0674

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.0830

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.0850

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 1 AN XY: 8

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.0911 AC: 13862 AN: 152202 Hom.: 816 Cov.: 32 AF XY: 0.0922 AC XY: 6864 AN XY: 74408

Gnomad4 AFR AF: 0.0953

Gnomad4 AMR AF: 0.0673

Gnomad4 ASJ AF: 0.0381

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.0592

Gnomad4 FIN AF: 0.0830

Gnomad4 NFE AF: 0.0845

Gnomad4 OTH AF: 0.0855

Alfa AF: 0.0513 Hom.: 53

Bravo AF: 0.0904

Asia WGS AF: 0.156 AC: 542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs2077777; hg19: chr4-26323918;