5-95780375-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014899.4(RHOBTB3):c.1406A>G(p.Glu469Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RHOBTB3 NM_014899.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.83

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31573743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHOBTB3	NM_014899.4	c.1406A>G	p.Glu469Gly	missense_variant	9/12	ENST00000379982.8
RHOBTB3	XM_011543279.3	c.1040A>G	p.Glu347Gly	missense_variant	8/11
RHOBTB3	XM_017009237.2	c.824A>G	p.Glu275Gly	missense_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHOBTB3	ENST00000379982.8	c.1406A>G	p.Glu469Gly	missense_variant	9/12	1	NM_014899.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727202

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

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 23, 2024

The c.1406A>G (p.E469G) alteration is located in exon 9 (coding exon 9) of the RHOBTB3 gene. This alteration results from a A to G substitution at nucleotide position 1406, causing the glutamic acid (E) at amino acid position 469 to be replaced by a glycine (G). 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	0.40
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D;D
Polyphen		0.83	P;.
Vest4		0.38
MutPred		0.51		Loss of methylation at K468 (P = 0.1395);.;
MVP		0.86
MPC		0.59
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr5-95116079;