22-23692990-C-T

Position:

• chr22-23692990-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153615.2(RGL4):​c.695C>T​(p.Ala232Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000903 in 1,594,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: RGL4 NM_153615.2 missense, splice_region
• Scores: Splicing: ADA: 0.004682
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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]

ENSG00000291299 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028927594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGL4	NM_153615.2	c.695C>T	p.Ala232Val	missense_variant, splice_region_variant	3/11	ENST00000290691.10	NP_705843.1
RGL4	NM_001329424.3	c.695C>T	p.Ala232Val	missense_variant, splice_region_variant	3/12		NP_001316353.1
GUSBP11	NR_024448.2	n.2561+1129G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGL4	ENST00000290691.10	c.695C>T	p.Ala232Val	missense_variant, splice_region_variant	3/11	1	NM_153615.2	ENSP00000290691.5
RGL4	ENST00000441897.5	n.695C>T		splice_region_variant, non_coding_transcript_exon_variant	5/14	2		ENSP00000396252.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000154 AC: 36 AN: 233708 Hom.: 0 AF XY: 0.000119 AC XY: 15 AN XY: 126388

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000384

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.0000485 AC: 70 AN: 1442336 Hom.: 0 Cov.: 33 AF XY: 0.0000322 AC XY: 23 AN XY: 714968

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74500

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000620 Hom.: 0

Bravo AF: 0.000480

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Aug 02, 2021

The c.695C>T (p.A232V) alteration is located in exon 3 (coding exon 3) of the RGL4 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the alanine (A) at amino acid position 232 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.7
DANN	Benign	0.91
DEOGEN2	Benign	0.051	.;.;.;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;.;L;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.1	D;.;.;D;D
REVEL	Benign	0.17
Sift	Benign	0.12	T;.;.;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.54	.;.;.;P;.
Vest4		0.17
MVP		0.38
MPC		0.14
ClinPred		0.091	T
GERP RS		-5.3
Varity_R		0.082
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0047
dbscSNV1_RF	Benign	0.22
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

LitVar

Other links and lift over

dbSNP: rs144310148; hg19: chr22-24035177;