Variant 12-49065120-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144593.3(RHEBL1):c.535C>T(p.Arg179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

RHEBL1
NM_144593.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.981

Variant links:

Genes affected

RHEBL1 (HGNC:21166): (RHEB like 1) Enables GTP binding activity. Involved in TOR signaling and positive regulation of NF-kappaB transcription factor activity. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RHEBL1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18587512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RHEBL1	NM_144593.3 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	8/8	ENST00000301068.11	NP_653194.1
RHEBL1	NM_001303126.2 linkuse as main transcript	c.529C>T	p.Arg177Cys	missense_variant	8/8		NP_001290055.1
RHEBL1	XM_047428286.1 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	7/7		XP_047284242.1
RHEBL1	NR_130123.2 linkuse as main transcript	n.661C>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHEBL1	ENST00000301068.11 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	8/8	1	NM_144593.3	ENSP00000301068	P1	Q8TAI7-1
RHEBL1	ENST00000420065.5 linkuse as main transcript	c.*338C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	1		ENSP00000409818
RHEBL1	ENST00000550797.1 linkuse as main transcript	c.*396C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	1		ENSP00000446726		Q8TAI7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251416

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461174

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726952

show subpopulations

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:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.535C>T (p.R179C) alteration is located in exon 8 (coding exon 8) of the RHEBL1 gene. This alteration results from a C to T substitution at nucleotide position 535, causing the arginine (R) at amino acid position 179 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

0.0059

Eigen_PC

Benign

-0.046

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.86

M_CAP

Benign

0.037

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

REVEL

Benign

0.20

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Polyphen

0.98

Vest4

0.15

MVP

0.71

MPC

0.85

ClinPred

0.23

GERP RS

2.5

Varity_R

0.087

gMVP

0.67

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

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