4-26334621-C-T

Variant names:

• chr4-26334621-C-T
• rs13144326
• NM_015874.6:c.20+13573C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000355476.8(RBPJ):​c.20+13573C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 151,944 control chromosomes in the GnomAD database, including 20,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: 𝑓 0.52 (20755 hom., cov: 31)
• Consequence: RBPJ ENST00000355476.8 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0460
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 4-26334621-C-T is Benign according to our data. Variant chr4-26334621-C-T is described in ClinVar as Benign. ClinVar VariationId is 444124.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355476.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	NM_015874.6	MANE Select	c.20+13573C>T		intron	N/A	NP_056958.3
	RBPJ	NM_001374400.1		c.59+13806C>T		intron	N/A	NP_001361329.1
	RBPJ	NM_005349.4		c.59+13806C>T		intron	N/A	NP_005340.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000355476.8	TSL:1 MANE Select	c.20+13573C>T		intron	N/A	ENSP00000347659.4
	RBPJ	ENST00000361572.10	TSL:1	c.59+13806C>T		intron	N/A	ENSP00000354528.6
	RBPJ	ENST00000348160.9	TSL:1	c.-167+13573C>T		intron	N/A	ENSP00000339699.5

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79186 AN: 151824 Hom.: 20723 Cov.: 31

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.513

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

GnomAD4 genome AF: 0.522 AC: 79269 AN: 151944 Hom.: 20755 Cov.: 31 AF XY: 0.521 AC XY: 38700 AN XY: 74248

African (AFR) AF: 0.491 AC: 20337 AN: 41420

American (AMR) AF: 0.573 AC: 8752 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1624 AN: 3468

East Asian (EAS) AF: 0.394 AC: 2029 AN: 5150

South Asian (SAS) AF: 0.467 AC: 2253 AN: 4820

European-Finnish (FIN) AF: 0.561 AC: 5930 AN: 10562

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.538 AC: 36565 AN: 67942

Other (OTH) AF: 0.508 AC: 1072 AN: 2110

Alfa AF: 0.520 Hom.: 8920

Bravo AF: 0.523

Asia WGS AF: 0.432 AC: 1507 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.0
DANN	Benign	0.72
PhyloP100		-0.046
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13144326; hg19: chr4-26336243;