ENST00000361572.10:c.20C>T

Variant names:

• chr4-26320776-C-T
• rs1215606918
• ENST00000361572.10:c.20C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000361572.10(RBPJ):​c.20C>T​(p.Ser7Leu) 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 1,402,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RBPJ ENST00000361572.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06605384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361572.10. 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_001379407.1		c.-206C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001366336.1	Q06330-6
	RBPJ	NM_001374400.1		c.20C>T	p.Ser7Leu	missense	Exon 2 of 12	NP_001361329.1	Q06330-1
	RBPJ	NM_005349.4		c.20C>T	p.Ser7Leu	missense	Exon 2 of 12	NP_005340.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000361572.10	TSL:1	c.20C>T	p.Ser7Leu	missense	Exon 1 of 11	ENSP00000354528.6	Q06330-1
	RBPJ	ENST00000345843.8	TSL:1	c.-47+888C>T		intron	N/A	ENSP00000305815.6	Q06330-5
	RBPJ	ENST00000342295.6	TSL:5	c.20C>T	p.Ser7Leu	missense	Exon 2 of 12	ENSP00000345206.1	Q06330-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402470 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691988

African (AFR) AF: 0.00 AC: 0 AN: 31934

American (AMR) AF: 0.00 AC: 0 AN: 35766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36246

South Asian (SAS) AF: 0.00 AC: 0 AN: 79548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1080578

Other (OTH) AF: 0.00 AC: 0 AN: 58138

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.26
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.051
Sift	Benign	0.59	T
Sift4G	Benign	0.36	T
Polyphen		0.83	P
Vest4		0.13
MutPred		0.20		Loss of phosphorylation at S7 (P = 0.0048)
MVP		0.36
MPC		0.96
ClinPred		0.27	T
GERP RS		1.8
PromoterAI		-0.064	Neutral
Varity_R		0.048
gMVP		0.27
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1215606918; hg19: chr4-26322398;