rs2070446

chr22-23693783-C-Gchr22-23693783-C-T

Variant summary

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

The NM_153615.2(RGL4):c.721C>G(p.His241Asp) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H241Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RGL4 NM_153615.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77

Genes affected

RGL4 (HGNC:31911): (ral guanine nucleotide dissociation stimulator like 4) This oncogene encodes a protein similar to guanine nucleotide exchange factor Ral guanine dissociation stimulator. Increased expression of this gene leads to translocation of the encoded protein to the cell membrane. The encoded protein can activate several pathways, including the Ras-Raf-MEK-ERK cascade. [provided by RefSeq, Jul 2016]

GUSBP11 (HGNC:42325): (GUSB pseudogene 11) This transcribed pseudogene is similar to two functional genes. The 5' portion of the pseudogene is related to glucuronidase, beta, and the 3' portion is related to immunoglobulin lambda-like polypeptide 1. [provided by RefSeq, Jul 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=0.2365449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGL4	NM_153615.2	c.721C>G	p.His241Asp	missense_variant	4/11	ENST00000290691.10
GUSBP11	NR_024448.2	n.2561+336G>C		intron_variant, non_coding_transcript_variant
RGL4	NM_001329424.3	c.721C>G	p.His241Asp	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGL4	ENST00000290691.10	c.721C>G	p.His241Asp	missense_variant	4/11	1	NM_153615.2	P2
GUSBP11	ENST00000435868.1	n.711+20428G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	12
Dann	Benign	0.81
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.82	T;T;D;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.1	D;.;.;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.010	D;.;.;D;D
Sift4G	Benign	0.11	T;D;D;T;D
Polyphen		0.56	.;.;.;P;.
Vest4		0.30
MutPred		0.41		.;.;.;Gain of relative solvent accessibility (P = 0.0507);Gain of relative solvent accessibility (P = 0.0507);
MVP		0.35
MPC		0.22
ClinPred		0.44	T
GERP RS		-1.1
Varity_R		0.19
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs2070446; hg19: chr22-24035970;