4-26320500-G-T

Variant summary

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

The ENST00000345843.8(RBPJ):c.-47+612G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 471,404 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: RBPJ ENST00000345843.8 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.979

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 4-26320500-G-T is Benign according to our data. Variant chr4-26320500-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1179953.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00819 (1247/152268) while in subpopulation AFR AF= 0.0283 (1177/41538). AF 95% confidence interval is 0.027. There are 12 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJ	NM_001374400.1	c.-57-200G>T		intron_variant
RBPJ	NM_001374401.1	c.-166-41946G>T		intron_variant
RBPJ	NM_001379406.1	c.-167+612G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJ	ENST00000345843.8	c.-47+612G>T		intron_variant		1
RBPJ	ENST00000342295.6	c.-57-200G>T		intron_variant		5
RBPJ	ENST00000506956.5	c.-167+730G>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152150 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00104 AC: 332 AN: 319136 Hom.: 3 AF XY: 0.000853 AC XY: 142 AN XY: 166466

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000414

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000152

Gnomad4 OTH exome AF: 0.00216

GnomAD4 genome AF: 0.00819 AC: 1247 AN: 152268 Hom.: 12 Cov.: 32 AF XY: 0.00806 AC XY: 600 AN XY: 74442

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00707 Hom.: 2

Bravo AF: 0.00955

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.61
Dann	Benign	0.77

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: rs28691136; hg19: chr4-26322122;