14-63283155-G-T

Position:

• chr14-63283155-G-T

Variant summary

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

The ENST00000316754.8(RHOJ):​c.437G>T​(p.Arg146Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOJ ENST00000316754.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25

Genes affected

RHOJ (HGNC:688): (ras homolog family member J) This gene encodes one of the many small GTP-binding proteins in the Rho family shown to be associated with focal adhesions in endothelial cells (PMID: 21148427, 22103495). The encoded protein is activated by vascular endothelial growth factor and may regulate angiogenesis. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOJ	NM_020663.5	c.437G>T	p.Arg146Leu	missense_variant	4/5	ENST00000316754.8	NP_065714.1
RHOJ	XM_047431613.1	c.437G>T	p.Arg146Leu	missense_variant	4/5		XP_047287569.1
RHOJ	XM_011536993.4	c.272G>T	p.Arg91Leu	missense_variant	3/4		XP_011535295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOJ	ENST00000316754.8	c.437G>T	p.Arg146Leu	missense_variant	4/5	1	NM_020663.5	ENSP00000316729.3
RHOJ	ENST00000555125.1	c.437G>T	p.Arg146Leu	missense_variant	4/4	2		ENSP00000451643.1
RHOJ	ENST00000557447.5	n.303+2119G>T		intron_variant		5		ENSP00000451796.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 14, 2024

The c.437G>T (p.R146L) alteration is located in exon 4 (coding exon 4) of the RHOJ gene. This alteration results from a G to T substitution at nucleotide position 437, causing the arginine (R) at amino acid position 146 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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.34	B;.
Vest4		0.65
MutPred		0.51		Gain of ubiquitination at K151 (P = 0.03);Gain of ubiquitination at K151 (P = 0.03);
MVP		0.72
MPC		0.29
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.60
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: chr14-63749873;