NM_015874.6:c.957C>A

Variant names:

• chr4-26429966-C-A
• rs1553882550
• NM_015874.6:c.957C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_015874.6(RBPJ):​c.957C>A​(p.Ser319Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBPJ NM_015874.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.820
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 4-26429966-C-A is Pathogenic according to our data. Variant chr4-26429966-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523588.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015874.6. 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.957C>A	p.Ser319Arg	missense	Exon 9 of 11	NP_056958.3
	RBPJ	NM_001374400.1		c.996C>A	p.Ser332Arg	missense	Exon 10 of 12	NP_001361329.1
	RBPJ	NM_005349.4		c.996C>A	p.Ser332Arg	missense	Exon 10 of 12	NP_005340.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000355476.8	TSL:1 MANE Select	c.957C>A	p.Ser319Arg	missense	Exon 9 of 11	ENSP00000347659.4
	RBPJ	ENST00000361572.10	TSL:1	c.996C>A	p.Ser332Arg	missense	Exon 9 of 11	ENSP00000354528.6
	RBPJ	ENST00000342320.8	TSL:1	c.954C>A	p.Ser318Arg	missense	Exon 9 of 11	ENSP00000340124.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Adams-Oliver syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.82
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.52		Gain of phosphorylation at T329 (P = 0.1088)
MVP		0.82
MPC		2.4
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.90
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1553882550; hg19: chr4-26431588;