chr4-26320782-C-T

Variant names:

• chr4-26320782-C-T
• rs1384718315
• ENST00000361572.10:c.26C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005349.4(RBPJ):​c.26C>T​(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RBPJ NM_005349.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.937
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12747544).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005349.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	NM_001374400.1		c.26C>T	p.Ala9Val	missense	Exon 2 of 12	NP_001361329.1	Q06330-1
	RBPJ	NM_005349.4		c.26C>T	p.Ala9Val	missense	Exon 2 of 12	NP_005340.2
	RBPJ	NM_001379408.1		c.26C>T	p.Ala9Val	missense	Exon 2 of 11	NP_001366337.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000361572.10	TSL:1	c.26C>T	p.Ala9Val	missense	Exon 1 of 11	ENSP00000354528.6	Q06330-1
	RBPJ	ENST00000345843.8	TSL:1	c.-47+894C>T		intron	N/A	ENSP00000305815.6	Q06330-5
	RBPJ	ENST00000342295.6	TSL:5	c.26C>T	p.Ala9Val	missense	Exon 2 of 12	ENSP00000345206.1	Q06330-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000628 AC: 1 AN: 159218 AF XY: 0.0000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000840

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402872 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692210

African (AFR) AF: 0.00 AC: 0 AN: 31960

American (AMR) AF: 0.00 AC: 0 AN: 35756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25198

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36324

South Asian (SAS) AF: 0.00 AC: 0 AN: 79590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080806

Other (OTH) AF: 0.00 AC: 0 AN: 58160

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.94
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.073
Sift	Benign	0.077	T
Sift4G	Benign	0.29	T
Polyphen		0.54	P
Vest4		0.17
MutPred		0.10		Loss of glycosylation at P12 (P = 0.0739)
MVP		0.69
MPC		1.1
ClinPred		0.31	T
GERP RS		3.0
PromoterAI		-0.11	Neutral
Varity_R		0.078
gMVP		0.19
Mutation Taster		=96/4	polymorphism

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: rs1384718315; hg19: chr4-26322404;