4-26320793-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000361572.10(RBPJ):c.37C>G(p.Pro13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,403,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RBPJ ENST00000361572.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.908

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RBPJ
• BP4: Computational evidence support a benign effect (MetaRNN=0.11934593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBPJ	NM_001374400.1	c.37C>G	p.Pro13Ala	missense_variant	2/12
RBPJ	NM_005349.4	c.37C>G	p.Pro13Ala	missense_variant	2/12
RBPJ	NM_001379408.1	c.37C>G	p.Pro13Ala	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBPJ	ENST00000361572.10	c.37C>G	p.Pro13Ala	missense_variant	1/11	1
RBPJ	ENST00000345843.8	c.-47+905C>G		intron_variant		1
RBPJ	ENST00000342295.6	c.37C>G	p.Pro13Ala	missense_variant	2/12	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1403656 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692632

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 10, 2023

Variant summary: RBPJ c.37C>G (p.Pro13Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 160606 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.37C>G in individuals affected with Adams-Oliver Syndrome 3 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Benign	0.96
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.52	T;T;.
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;N;N
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.019	.;B;B
Vest4		0.17, 0.14
MutPred		0.32		Loss of glycosylation at P13 (P = 0.0133);Loss of glycosylation at P13 (P = 0.0133);Loss of glycosylation at P13 (P = 0.0133);
MVP		0.53
MPC		1.0
ClinPred		0.13	T
GERP RS		2.0
Varity_R		0.037
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs1722936793; hg19: chr4-26322415;