Variant 12-49069037-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_144593.3(RHEBL1):c.122A>G(p.Asn41Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RHEBL1
NM_144593.3 missense, splice_region

Scores

Splicing: ADA: 0.3822

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a mutagenesis_site Partially impaired in RPS6K1 activation. (size 0) in uniprot entity REBL1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2279062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHEBL1	NM_144593.3 linkuse as main transcript	c.122A>G	p.Asn41Ser	missense_variant, splice_region_variant	2/8	ENST00000301068.11	NP_653194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHEBL1	ENST00000301068.11 linkuse as main transcript	c.122A>G	p.Asn41Ser	missense_variant, splice_region_variant	2/8	1	NM_144593.3	ENSP00000301068	P1	Q8TAI7-1
RHEBL1	ENST00000550797.1 linkuse as main transcript	c.190A>G	p.Ile64Val	missense_variant, splice_region_variant, NMD_transcript_variant	2/8	1		ENSP00000446726		Q8TAI7-2
RHEBL1	ENST00000420065.5 linkuse as main transcript	c.122A>G	p.Asn41Ser	missense_variant, splice_region_variant, NMD_transcript_variant	2/7	1		ENSP00000409818
RHEBL1	ENST00000550675.1 linkuse as main transcript	c.122A>G	p.Asn41Ser	missense_variant, splice_region_variant	2/5	5		ENSP00000447428

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461098

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726818

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2023

The c.122A>G (p.N41S) alteration is located in exon 2 (coding exon 2) of the RHEBL1 gene. This alteration results from a A to G substitution at nucleotide position 122, causing the asparagine (N) at amino acid position 41 to be replaced by a serine (S). 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

0.28

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

0.050

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.78

N;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.30

Sift

Benign

0.070

T;D

Sift4G

Benign

0.085

T;.

Polyphen

0.81

P;B

Vest4

0.061

MutPred

0.70

Gain of disorder (P = 0.0494);Gain of disorder (P = 0.0494);

MVP

0.53

MPC

0.33

ClinPred

0.57

GERP RS

3.8

Varity_R

0.37

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.38

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over