Variant 11-73392283-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152222.2(RELT):c.440C>T(p.Pro147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,613,196 control chromosomes in the GnomAD database, including 3 homozygotes. 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: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 3 hom. )

Consequence

RELT
NM_152222.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.677

Variant links:

Genes affected

RELT (HGNC:13764): (RELT TNF receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is especially abundant in hematologic tissues. It has been shown to activate the NF-kappaB pathway and selectively bind TNF receptor-associated factor 1 (TRAF1). This receptor is capable of stimulating T-cell proliferation in the presence of CD3 signaling, which suggests its regulatory role in immune response. Two alternatively spliced transcript variants of this gene encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

RELT links:

RELT (HGNC:):

RELT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040820003).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELT	NM_152222.2 linkuse as main transcript	c.440C>T	p.Pro147Leu	missense_variant	6/11	ENST00000064780.7	NP_689408.1	Q969Z4A0A024R5N3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RELT	ENST00000064780.7 linkuse as main transcript	c.440C>T	p.Pro147Leu	missense_variant	6/11	1	NM_152222.2	ENSP00000064780.2	Q969Z4
RELT	ENST00000393580.2 linkuse as main transcript	c.440C>T	p.Pro147Leu	missense_variant	6/11	1		ENSP00000377207.2	Q969Z4
RELT	ENST00000545886.1 linkuse as main transcript	n.302C>T		non_coding_transcript_exon_variant	1/3	2
RELT	ENST00000544075.5 linkuse as main transcript	n.287+1362C>T		intron_variant		3		ENSP00000440562.1	F5GYS9

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000234

AC:

AN:

247716

Hom.:

AF XY:

0.000208

AC XY:

AN XY:

134614

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000529

AC:

773

AN:

1460858

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

343

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000668

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000282

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000360

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.440C>T (p.P147L) alteration is located in exon 6 (coding exon 5) of the RELT gene. This alteration results from a C to T substitution at nucleotide position 440, causing the proline (P) at amino acid position 147 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.70

.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.13

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.0010

B;B

Vest4

0.17

MVP

0.57

MPC

0.11

ClinPred

0.16

GERP RS

3.7

Varity_R

0.15

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over