4-26320420-G-A

Variant names:

• chr4-26320420-G-A
• rs7657866
• ENST00000345843.8:c.-47+532G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005349.4(RBPJ):​c.-57-280G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 342,192 control chromosomes in the GnomAD database, including 7,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4971 hom., cov: 32)
  • Exomes 𝑓: 0.13 (2366 hom.)
• Consequence: RBPJ NM_005349.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.902
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 4-26320420-G-A is Benign according to our data. Variant chr4-26320420-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

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.-57-280G>A		intron	N/A	NP_001361329.1	Q06330-1
	RBPJ	NM_005349.4		c.-57-280G>A		intron	N/A	NP_005340.2
	RBPJ	NM_001374401.1		c.-166-42026G>A		intron	N/A	NP_001361330.1	Q06330-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBPJ	ENST00000345843.8	TSL:1	c.-47+532G>A		intron	N/A	ENSP00000305815.6	Q06330-5
	RBPJ	ENST00000342295.6	TSL:5	c.-57-280G>A		intron	N/A	ENSP00000345206.1	Q06330-1
	RBPJ	ENST00000512671.6	TSL:2	c.-57-280G>A		intron	N/A	ENSP00000423644.2	Q06330-1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30539 AN: 151934 Hom.: 4956 Cov.: 32

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0603

Gnomad EAS AF: 0.342

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0946

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0958

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.127 AC: 24165 AN: 190140 Hom.: 2366 AF XY: 0.122 AC XY: 11979 AN XY: 97806

African (AFR) AF: 0.445 AC: 2521 AN: 5668

American (AMR) AF: 0.110 AC: 791 AN: 7166

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 406 AN: 7110

East Asian (EAS) AF: 0.347 AC: 5127 AN: 14754

South Asian (SAS) AF: 0.0727 AC: 790 AN: 10862

European-Finnish (FIN) AF: 0.105 AC: 1343 AN: 12798

Middle Eastern (MID) AF: 0.0840 AC: 82 AN: 976

European-Non Finnish (NFE) AF: 0.0957 AC: 11322 AN: 118328

Other (OTH) AF: 0.143 AC: 1783 AN: 12478

GnomAD4 genome AF: 0.201 AC: 30596 AN: 152052 Hom.: 4971 Cov.: 32 AF XY: 0.200 AC XY: 14861 AN XY: 74326

African (AFR) AF: 0.444 AC: 18395 AN: 41438

American (AMR) AF: 0.124 AC: 1892 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0603 AC: 209 AN: 3468

East Asian (EAS) AF: 0.341 AC: 1752 AN: 5132

South Asian (SAS) AF: 0.0744 AC: 359 AN: 4826

European-Finnish (FIN) AF: 0.0946 AC: 1003 AN: 10606

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0958 AC: 6514 AN: 67992

Other (OTH) AF: 0.179 AC: 377 AN: 2106

Alfa AF: 0.184 Hom.: 1299

Bravo AF: 0.216

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.4
DANN	Benign	0.67
PhyloP100		0.90
PromoterAI		-0.010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs7657866; hg19: chr4-26322042;