chr22-23694349-G-C

Position:

• chr22-23694349-G-C

Variant summary

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

The NM_153615.2(RGL4):​c.915G>C​(p.Glu305Asp) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGL4 NM_153615.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42205974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGL4	NM_153615.2	c.915G>C	p.Glu305Asp	missense_variant, splice_region_variant	5/11	ENST00000290691.10
GUSBP11	NR_024448.2	n.2331C>G		non_coding_transcript_exon_variant	8/12
RGL4	NM_001329424.3	c.915G>C	p.Glu305Asp	missense_variant, splice_region_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGL4	ENST00000290691.10	c.915G>C	p.Glu305Asp	missense_variant, splice_region_variant	5/11	1	NM_153615.2	P2
GUSBP11	ENST00000435868.1	n.711+19862C>G		intron_variant, non_coding_transcript_variant

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

Nov 13, 2023

The c.915G>C (p.E305D) alteration is located in exon 5 (coding exon 5) of the RGL4 gene. This alteration results from a G to C substitution at nucleotide position 915, causing the glutamic acid (E) at amino acid position 305 to be replaced by an aspartic acid (D). 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	0.48
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.84	T;T;D;D;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D;.;.;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;.;.;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.88	.;.;.;P;.
Vest4		0.30
MutPred		0.63		.;.;.;Gain of MoRF binding (P = 0.1044);Gain of MoRF binding (P = 0.1044);
MVP		0.49
MPC		0.36
ClinPred		0.95	D
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr22-24036536;