chr5-95783805-T-C

Position:

• chr5-95783805-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000379982.8(RHOBTB3):​c.1465T>C​(p.Phe489Leu) 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 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)
• Consequence: RHOBTB3 ENST00000379982.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

Genes affected

RHOBTB3 (HGNC:18757): (Rho related BTB domain containing 3) Enables ATP binding activity and small GTPase binding activity. Involved in retrograde transport, endosome to Golgi. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

GLRX (HGNC:4330): (glutaredoxin) This gene encodes a member of the glutaredoxin family. The encoded protein is a cytoplasmic enzyme catalyzing the reversible reduction of glutathione-protein mixed disulfides. This enzyme highly contributes to the antioxidant defense system. It is crucial for several signalling pathways by controlling the S-glutathionylation status of signalling mediators. It is involved in beta-amyloid toxicity and Alzheimer's disease. Multiple alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2011]

RHOBTB3 (HGNC:):

ACMG classification

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=0.07836741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOBTB3	NM_014899.4	c.1465T>C	p.Phe489Leu	missense_variant	10/12	ENST00000379982.8	NP_055714.3
RHOBTB3	XM_011543279.3	c.1099T>C	p.Phe367Leu	missense_variant	9/11		XP_011541581.1
RHOBTB3	XM_017009237.2	c.883T>C	p.Phe295Leu	missense_variant	10/12		XP_016864726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOBTB3	ENST00000379982.8	c.1465T>C	p.Phe489Leu	missense_variant	10/12	1	NM_014899.4	ENSP00000369318.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.1465T>C (p.F489L) alteration is located in exon 10 (coding exon 10) of the RHOBTB3 gene. This alteration results from a T to C substitution at nucleotide position 1465, causing the phenylalanine (F) at amino acid position 489 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	0.83	.;T
Polyphen		0.0	B;.
Vest4		0.18
MutPred		0.52		Loss of loop (P = 0.0986);.;
MVP		0.65
MPC		0.47
ClinPred		0.60	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.41

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: chr5-95119509;