rs1553878211

Positions:

• chr4-26406269-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_015874.6(RBPJ):​c.154A>G​(p.Arg52Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBPJ NM_015874.6 missense, splice_region
• Scores: Splicing: ADA: 0.6103
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.55

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RBPJ. . Gene score misZ 3.5749 (greater than the threshold 3.09). Trascript score misZ 3.8981 (greater than threshold 3.09). GenCC has associacion of gene with Adams-Oliver syndrome 3, Adams-Oliver syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 4-26406269-A-G is Pathogenic according to our data. Variant chr4-26406269-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBPJ	NM_015874.6	c.154A>G	p.Arg52Gly	missense_variant, splice_region_variant	3/11	ENST00000355476.8	NP_056958.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBPJ	ENST00000355476.8	c.154A>G	p.Arg52Gly	missense_variant, splice_region_variant	3/11	1	NM_015874.6	ENSP00000347659	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1433922 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 715380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Type 2 diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Adams-Oliver syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Centre of Medical Genetics, University of Antwerp

Dec 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D;.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;D;D;.;D;.;.;.;.;.;.;D;D;.
Vest4		0.98, 0.97, 0.98
MutPred		0.75		.;.;.;Gain of ubiquitination at K64 (P = 0.0358);.;Gain of ubiquitination at K64 (P = 0.0358);Gain of ubiquitination at K64 (P = 0.0358);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		1.1
Varity_R		0.96
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.55
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: rs1553878211; hg19: chr4-26407891;