4-26359946-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_015874.6(RBPJ):c.21-26407G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 152,282 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: 𝑓 0.027 (124 hom., cov: 32)
• Consequence: RBPJ NM_015874.6 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.147

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=-0.88).
• BP6: Variant 4-26359946-G-A is Benign according to our data. Variant chr4-26359946-G-A is described in ClinVar as [Benign]. Clinvar id is 444129.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-26359946-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJ	NM_015874.6	c.21-26407G>A		intron_variant		ENST00000355476.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJ	ENST00000355476.8	c.21-26407G>A		intron_variant		1	NM_015874.6	P4

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4135 AN: 152164 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.00787

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0870

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0314

Gnomad OTH AF: 0.0220

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

GnomAD4 genome AF: 0.0272 AC: 4144 AN: 152282 Hom.: 124 Cov.: 32 AF XY: 0.0282 AC XY: 2099 AN XY: 74470

Gnomad4 AFR AF: 0.00784

Gnomad4 AMR AF: 0.0875

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00662

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.0314

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0287 Hom.: 18

Bravo AF: 0.0318

Asia WGS AF: 0.00751 AC: 26 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	-0.88
Cadd	Benign	9.4
Dann	Benign	0.75

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: rs73245775; hg19: chr4-26361568;