4-26320652-A-G

Position:

• chr4-26320652-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000361572.10(RBPJ):​c.-105A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,376,112 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 33)
  • Exomes 𝑓: 0.019 (284 hom.)
• Consequence: RBPJ ENST00000361572.10 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.99

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-26320652-A-G is Benign according to our data. Variant chr4-26320652-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1197001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0139 (2114/151972) while in subpopulation SAS AF= 0.0358 (172/4802). AF 95% confidence interval is 0.0314. There are 26 homozygotes in gnomad4. There are 1039 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBPJ	NM_001374400.1	c.-57-48A>G		intron_variant			NP_001361329.1
RBPJ	NM_001374401.1	c.-166-41794A>G		intron_variant			NP_001361330.1
RBPJ	NM_001379406.1	c.-167+764A>G		intron_variant			NP_001366335.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJ	ENST00000361572.10	c.-105A>G		5_prime_UTR_variant	1/11	1		ENSP00000354528
RBPJ	ENST00000345843.8	c.-47+764A>G		intron_variant		1		ENSP00000305815
RBPJ	ENST00000342295.6	c.-57-48A>G		intron_variant		5		ENSP00000345206

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2115 AN: 151854 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.0187 AC: 22833 AN: 1224140 Hom.: 284 Cov.: 18 AF XY: 0.0195 AC XY: 11654 AN XY: 598654

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.0372

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0139 AC: 2114 AN: 151972 Hom.: 26 Cov.: 33 AF XY: 0.0140 AC XY: 1039 AN XY: 74288

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.0358

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0162

Alfa AF: 0.0155 Hom.: 6

Bravo AF: 0.0120

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.86

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: rs76524079; hg19: chr4-26322274;