5-95755592-T-G

Position:

• chr5-95755592-T-G

Variant summary

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

The ENST00000379982.8(RHOBTB3):​c.879T>G​(p.Ile293Met) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I293V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHOBTB3 ENST00000379982.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.449

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]

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=0.13212845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOBTB3	NM_014899.4	c.879T>G	p.Ile293Met	missense_variant	6/12	ENST00000379982.8	NP_055714.3
RHOBTB3	XM_017009237.2	c.297T>G	p.Ile99Met	missense_variant	6/12		XP_016864726.1
RHOBTB3	XM_011543279.3	c.682+3242T>G		intron_variant			XP_011541581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOBTB3	ENST00000379982.8	c.879T>G	p.Ile293Met	missense_variant	6/12	1	NM_014899.4	ENSP00000369318	P1
GLRX	ENST00000508780.5	c.*7-4132A>C		intron_variant		4		ENSP00000422708	P1
RHOBTB3	ENST00000504949.1	n.1010T>G		non_coding_transcript_exon_variant	6/6	2
RHOBTB3	ENST00000502541.1	c.*179T>G		3_prime_UTR_variant, NMD_transcript_variant	3/4	5		ENSP00000421875

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Feb 23, 2023

The c.879T>G (p.I293M) alteration is located in exon 6 (coding exon 6) of the RHOBTB3 gene. This alteration results from a T to G substitution at nucleotide position 879, causing the isoleucine (I) at amino acid position 293 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.10
Sift	Benign	0.050	D
Polyphen		0.50	P
Vest4		0.24
MutPred		0.39		Loss of helix (P = 0.0196);
MVP		0.55
MPC		0.61
ClinPred		0.37	T
GERP RS		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.24

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: chr5-95091296;