20-45314116-C-T

Variant names:

• chr20-45314116-C-T
• rs200998587
• NM_014276.4:c.839C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014276.4(RBPJL):​c.839C>T​(p.Thr280Met) variant causes a missense change. The variant allele was found at a frequency of 0.000428 in 1,614,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: RBPJL NM_014276.4 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.14

Genes affected

RBPJL (HGNC:13761): (recombination signal binding protein for immunoglobulin kappa J region like) This gene encodes a member of the suppressor of hairless protein family. A similar protein in mouse is a transcription factor that binds to DNA sequences almost identical to that bound by the Notch receptor signaling pathway transcription factor recombining binding protein J. The mouse protein has been shown to activate transcription in concert with Epstein-Barr virus nuclear antigen-2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009372294).
• BS2: High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBPJL	NM_014276.4	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12	ENST00000343694.8	NP_055091.2
RBPJL	NM_001281449.2	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12		NP_001268378.1
RBPJL	NM_001281448.2	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12		NP_001268377.1
RBPJL	XM_011528522.3	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12		XP_011526824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBPJL	ENST00000343694.8	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12	1	NM_014276.4	ENSP00000341243.3
RBPJL	ENST00000372743.5	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12	1		ENSP00000361828.1
RBPJL	ENST00000372741.7	c.839C>T	p.Thr280Met	missense_variant	Exon 8 of 12	1		ENSP00000361826.3
RBPJL	ENST00000464504.2	c.80C>T	p.Thr27Met	missense_variant	Exon 1 of 5	3		ENSP00000483978.1

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00327

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00166 AC: 418 AN: 251118 AF XY: 0.00124

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000421 AC: 616 AN: 1461680 Hom.: 1 Cov.: 31 AF XY: 0.000358 AC XY: 260 AN XY: 727176

Gnomad4 AFR exome AF: 0.000119 AC: 4 AN: 33476

Gnomad4 AMR exome AF: 0.0105 AC: 468 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53370

Gnomad4 NFE exome AF: 0.000111 AC: 123 AN: 1111864

Gnomad4 Remaining exome AF: 0.000348 AC: 21 AN: 60390

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74498

Gnomad4 AFR AF: 0.000265 AC: 0.000264563 AN: 0.000264563

Gnomad4 AMR AF: 0.00346 AC: 0.00346224 AN: 0.00346224

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000132 AC: 0.000132295 AN: 0.000132295

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00121 AC: 147

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Type 2 diabetes mellitus Other:1

-

Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institutes of Health

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: case-control

The variant allele associates with increased risk of T2D. In in-vtro studies the variant allele reduces protein expression and also effects tranactivation capability -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.55
MVP		0.34
MPC		1.2
ClinPred		0.081	T
GERP RS		5.3
Varity_R		0.34
gMVP		0.38
Mutation Taster		=55/45	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

Publications

LitVar

Other links and lift over

dbSNP: rs200998587; hg19: chr20-43942756;