22-23696660-T-C

Variant names:

• chr22-23696660-T-C
• rs1007298
• NM_153615.2:c.1133T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153615.2(RGL4):​c.1133T>C​(p.Val378Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,612,944 control chromosomes in the GnomAD database, including 401,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (43734 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357343 hom.)
• Consequence: RGL4 NM_153615.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.872

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:):

ENSG00000272578 (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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.928761E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGL4	NM_153615.2	c.1133T>C	p.Val378Ala	missense_variant	Exon 7 of 11	ENST00000290691.10	NP_705843.1
RGL4	NM_001329424.3	c.1133T>C	p.Val378Ala	missense_variant	Exon 7 of 12		NP_001316353.1
RGL4	NM_001329425.2	c.-5T>C		5_prime_UTR_variant	Exon 2 of 6		NP_001316354.1
GUSBP11	NR_024448.2	n.1163-1143A>G		intron_variant	Intron 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGL4	ENST00000290691.10	c.1133T>C	p.Val378Ala	missense_variant	Exon 7 of 11	1	NM_153615.2	ENSP00000290691.5
RGL4	ENST00000441897.5	n.1300T>C		non_coding_transcript_exon_variant	Exon 10 of 14	2		ENSP00000396252.1

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114473 AN: 151968 Hom.: 43680 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.751

GnomAD3 exomes AF: 0.716 AC: 178895 AN: 249848 Hom.: 64476 AF XY: 0.712 AC XY: 96342 AN XY: 135228

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.759

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.676

Gnomad SAS exome AF: 0.741

Gnomad FIN exome AF: 0.674

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.698 AC: 1019818 AN: 1460858 Hom.: 357343 Cov.: 49 AF XY: 0.699 AC XY: 508084 AN XY: 726760

Gnomad4 AFR exome AF: 0.894

Gnomad4 AMR exome AF: 0.762

Gnomad4 ASJ exome AF: 0.767

Gnomad4 EAS exome AF: 0.696

Gnomad4 SAS exome AF: 0.740

Gnomad4 FIN exome AF: 0.668

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.718

GnomAD4 genome AF: 0.753 AC: 114587 AN: 152086 Hom.: 43734 Cov.: 32 AF XY: 0.753 AC XY: 55968 AN XY: 74340

Gnomad4 AFR AF: 0.888

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.774

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.746

Gnomad4 FIN AF: 0.681

Gnomad4 NFE AF: 0.684

Gnomad4 OTH AF: 0.752

Alfa AF: 0.699 Hom.: 75250

Bravo AF: 0.763

TwinsUK AF: 0.683 AC: 2532

ALSPAC AF: 0.691 AC: 2665

ESP6500AA AF: 0.891 AC: 3925

ESP6500EA AF: 0.691 AC: 5944

ExAC AF: 0.715 AC: 86785

Asia WGS AF: 0.706 AC: 2457 AN: 3478

EpiCase AF: 0.693

EpiControl AF: 0.694

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.0
DANN	Benign	0.88
DEOGEN2	Benign	0.019	.;.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.15	T;T;T;T;T
MetaRNN	Benign	7.9e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	.;.;.;N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.0	N;.;.;N;N
REVEL	Benign	0.047
Sift	Benign	1.0	T;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;.;.;B;.
Vest4		0.095
MPC		0.089
ClinPred		0.0068	T
GERP RS		-0.41
Varity_R		0.034
gMVP		0.066

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: rs1007298; hg19: chr22-24038847; COSMIC: COSV51944756; COSMIC: COSV51944756;