4-26365497-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015874.6(RBPJ):c.21-20856T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 152,332 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: 𝑓 0.0037 (5 hom., cov: 32)
• Consequence: RBPJ NM_015874.6 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0670

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-26365497-T-C is Benign according to our data. Variant chr4-26365497-T-C is described in ClinVar as [Benign]. Clinvar id is 444131.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00366 (557/152332) while in subpopulation EAS AF= 0.0334 (173/5180). AF 95% confidence interval is 0.0293. There are 5 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 556 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJ	NM_015874.6	c.21-20856T>C		intron_variant		ENST00000355476.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJ	ENST00000355476.8	c.21-20856T>C		intron_variant		1	NM_015874.6	P4

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152214 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00382

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00361 AC XY: 269 AN XY: 74492

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00482

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Type 2 diabetes mellitus Benign:1

Benign, no assertion criteria provided

case-control

Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institutes of Health

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.7
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: rs78672655; hg19: chr4-26367119;