11-73392364-T-G

Position:

• chr11-73392364-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_152222.2(RELT):​c.521T>G​(p.Leu174Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RELT NM_152222.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.91

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 11-73392364-T-G is Pathogenic according to our data. Variant chr11-73392364-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573118.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELT	NM_152222.2	c.521T>G	p.Leu174Arg	missense_variant	6/11	ENST00000064780.7	NP_689408.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELT	ENST00000064780.7	c.521T>G	p.Leu174Arg	missense_variant	6/11	1	NM_152222.2	ENSP00000064780.2
RELT	ENST00000393580.2	c.521T>G	p.Leu174Arg	missense_variant	6/11	1		ENSP00000377207.2
RELT	ENST00000545886.1	n.383T>G		non_coding_transcript_exon_variant	1/3	2
RELT	ENST00000544075.5	n.287+1443T>G		intron_variant		3		ENSP00000440562.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amelogenesis imperfecta Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department Of Pediatric Dentistry, Peking University School And Hospital Of Stomatology

May 20, 2023

Homozygous mutations in RELT have been reported to cause autosomal recessive AI. Multiple missense mutations have been reported to be associated with AI. The variant cosegregation with the disease in this family. The RELT variant (c.521T>G) is absent in the dbSNP database and the 1000 Genomes Project Consortium. It was predicted to be damaging by SIFT (0.001, Deleterious), Polyphen2_HDIV (0.999, Probably damaging), MutationTaster (0.99, Disease-causing) and CADD (score: 28.7). These nucleotide change in RELT were absent in 144 ethnically matched normal controls. Amino-acid alignment analysis revealed that the affected residues were highly conserved among different species. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.76
MutPred		0.68		Gain of MoRF binding (P = 0.0354);Gain of MoRF binding (P = 0.0354);
MVP		0.73
MPC		0.64
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-73103409;